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BIOMARKER:

FLT3 F691L

i
Other names: FLT3, Fms Related Tyrosine Kinase 3, Receptor-Type Tyrosine-Protein Kinase FLT3, Stem Cell Tyrosine Kinase 1, Fms-Like Tyrosine Kinase 3, CD135, FLK-2, STK1, Growth Factor Receptor Tyrosine Kinase Type III, Fetal Liver Kinase 2
Entrez ID:
2ms
Identification of furo[2,3-d]pyrimidin-4-ylsulfanyl-1,3,4-thiadiazole derivatives as novel FLT3-ITD inhibitors. (PubMed, Eur J Med Chem)
Notably, compound 49 demonstrated cytotoxic effects in Ba/F3 cells expressing FLT3-ITD or FLT3-ITD-F691L mutant, exceeding the potency of both sorafenib and quizartinib. The study suggests that substituted furo[2,3-d]pyrimidines could be useful additions to the growing field of FLT3-targeted therapy for AML. These compounds have the potential to serve as novel FLT3-ITD inhibitors and may offer insights for developing future therapeutic strategies in AML.
Journal
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3-ITD mutation • FLT3 F691L • FLT3 expression • FLT3-ITD expression • FLT3-ITD mutation + FLT3 F691L
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sorafenib • Vanflyta (quizartinib)
3ms
Concentration of gilteritinib in the cerebrospinal fluid of a patient with relapsed FLT3-ITD positive acute myeloid leukemia with optic nerve involvement (PubMed, Rinsho Ketsueki)
In this patient, pharmacokinetic (low CNS penetration of gilteritinib) and pharmacodynamic (acquisition of a drug resistance mutation) mechanisms were thought to be responsible for the CNS relapse and hematologic PD, respectively. We believe this is a valuable case to report considering the scarcity of data on CNS penetration of FLT3 inhibitors and their effects on CNS disease in the literature.
Journal
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3 F691L
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Xospata (gilteritinib)
7ms
Structure-Based Optimization of Pyrazinamide-Containing Macrocyclic Derivatives as Fms-like Tyrosine Kinase 3 (FLT3) Inhibitors to Overcome Clinical Mutations. (PubMed, ACS Pharmacol Transl Sci)
Furthermore, 8v demonstrated ideal anticancer efficacy in a Ba/F3-FLT3-ITD-D835Y xenograft model. The results suggested that 8v can serve as a promising macrocycle-based FLT3 inhibitor for the treatment of AML.
Journal
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3 mutation • FLT3 D835Y • FLT3 F691L • FLT3 D835 • FLT3-ITD mutation + FLT3 D835Y + FLT3 F691L
12ms
An imidazo[1,2-a]pyridine-pyridine derivative potently inhibits FLT3-ITD and FLT3-ITD secondary mutants, including gilteritinib-resistant FLT3-ITD/F691L. (PubMed, Eur J Med Chem)
Recently, several FLT3 inhibitors have demonstrated clinical activity and three are currently approved - midostaurin, quizartinib, and gilteritinib. In summary, compound 24 has inhibition potency on FLT3 comparable to gilteritinib, but a more balanced inhibition on FLT3 secondary mutations, especially FLT3-ITD/F691L which is gilteritinib resistant. Compound 24 may serve as a promising lead for the drug development of either primary or relapsed AML with FLT3 secondary mutations.
Journal
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3-ITD mutation • FLT3 mutation • FLT3 D835Y • FLT3 F691L • FLT3 D835
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Xospata (gilteritinib) • Rydapt (midostaurin) • Vanflyta (quizartinib)
1year
A Phase 1a/b Trial of Luxeptinib (CG-806) in Patients with Relapsed/Refractory B-Cell Malignancies or Acute Myeloid Leukemia and Evaluation of New G3 Formulation (ASH 2023)
Introduction: Luxeptinib (CG-806; LUX) is an orally active noncovalent kinase inhibitor of Bruton's tyrosine kinase (BTK), wild type and mutant forms of Fms-like tyrosine kinase 3 (FLT3) (including the internal tandem duplicates (ITD), tyrosine kinase domain (TKD), and F691L mutant forms), and growth receptors like KIT, CSF1R, PDGFRα, and TRKs. LUX has a favorable safety profile in patients at all tested dose levels, for multiple cycles, for both studies. Antitumor activity was observed in a heavily pretreated relapsed AML patient and in multiple B-NHL subtypes and CLL/SLL patients including several with prior ibrutinib exposure. Continuous dosing of patients with R/R AML and Higher-Risk MDS with the G3 formulation is ongoing; with updated clinical data (200 mg dose level) to be presented at the meeting.
Clinical • P1 data
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FLT3 (Fms-related tyrosine kinase 3) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • LYN (LYN Proto-Oncogene Src Family Tyrosine Kinase) • SYK (Spleen tyrosine kinase) • CSF1R (Colony stimulating factor 1 receptor)
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FLT3 F691L
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Imbruvica (ibrutinib) • luxeptinib (CG-806)
1year
GNF-7, a novel FLT3 inhibitor, overcomes drug resistance for the treatment of FLT3‑ITD acute myeloid leukemia. (PubMed, Cancer Cell Int)
Our results show that GNF-7 is a potent FLT3-ITD inhibitor and may become a promising lead compound applied for treating some of the clinically drug resistant patients.
Journal
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3-ITD mutation • FLT3 mutation • FLT3 F691L • FLT3 expression • FLT3-ITD expression • FLT3-ITD mutation + FLT3 F691L
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Xospata (gilteritinib) • Vanflyta (quizartinib)
1year
Discovery of benzimidazole-indazole derivatives as potent FLT3-tyrosine kinase domain mutant kinase inhibitors for acute myeloid leukemia. (PubMed, Eur J Med Chem)
More importantly, 22f showed single-digit nanomolar GI values in the mutant FLT kinase expressed Ba/F3 cell lines including FLT-D835Y (GI = 0.29 nM) and FLT3-F691L (GI = 2.87 nM). Molecular docking studies indicated that the compound exhibits a well-fitted binding mode as a type 1 inhibitor in the homology model of active conformation of FLT3 kinase.
Journal
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3 mutation • FLT3 D835Y • FLT3 F691L • FLT3 D835
1year
N-(3-Methoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine is an inhibitor of the FLT3-ITD and BCR-ABL pathways, and potently inhibits FLT3-ITD/D835Y and FLT3-ITD/F691L secondary mutants. (PubMed, Bioorg Chem)
Studies indicate that it mediates proapoptotic effects on cells by inhibiting FLT3 and BCR-ABL pathways, and other possible targets. Compound 1 is more potent against FLT3-ITD than BCR-ABL, and it may have other possible targets; however, compound 1 is first step for further optimization for the development of a balanced FLT3-ITD/BCR-ABL dual inhibitor for the treatment of relapsed FLT3-ITD mutated AML with multiple secondary clinical resistant subtypes such as FLT3-ITD/D835Y, FLT3-ITD/F691L, and cells co-expressing FLT3-ITD and BCR-ABL.
Journal
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FLT3 (Fms-related tyrosine kinase 3) • ABL1 (ABL proto-oncogene 1) • BCR (BCR Activator Of RhoGEF And GTPase)
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FLT3-ITD mutation • FLT3 mutation • FLT3 D835Y • FLT3 F691L • FLT3 D835 • FLT3 expression • FLT3-ITD expression
1year
BGS-2456 Is a Novel Potent Covalent Inhibitor of FLT3 That Highly Discriminates Against KIT and Is Not Toxic Toward Normal Hematopoiesis in Vitro (ASH 2023)
While there are numerous examples of KIT TKIs that do not inhibit FLT3 (imatinib, avapritinib, dasatinib), to date, all clinically active FLT3 TKIs (quizartinib, gilteritinib, midostaurin, sorafenib) fail to spare KIT inhibition...Compared to FF-10101 and gilteritinib, BGS-2456 exhibited the least amount of hematologic toxicity, facilitating in vitro proliferation and differentiation of normal hematopoietic progenitor cells even at 100x EC50 concentration against Molm14 cells... This is the first description of a potent and exquisitely specific FLT3 inhibitor that spares KIT inhibition and displays no myelosuppression in vitro at >100x EC50 concentration. The potent inhibitory effects of BGS-2456 on both D835Y and F691L mutants support its promise as a best-in-class TKI for the treatment of FLT3-mutant AML. Efforts to molecularly dissect the basis of the high degree of selectivity of BGS-2456 are ongoing.
Preclinical
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FLT3 (Fms-related tyrosine kinase 3) • ABL1 (ABL proto-oncogene 1) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • CSF1R (Colony stimulating factor 1 receptor)
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FLT3-ITD mutation • FLT3 mutation • KIT mutation • FLT3 D835Y • FLT3 F691L • FLT3 D835 • PDGFRA mutation • FLT3 D835V • FLT3 F691L + FLT3 D835V • FLT3-ITD mutation + FLT3 D835Y + FLT3 F691L
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dasatinib • sorafenib • imatinib • Xospata (gilteritinib) • Rydapt (midostaurin) • Vanflyta (quizartinib) • Ayvakit (avapritinib) • FF-10101 • BGS-2456
1year
Therapeutic Targeting of FLT3 Gate Keeper Mutation with E2082-0047 in Traditional and a Novel Immunocompetent Murine Adoptive Transfer Model of AML (ASH 2023)
Guided by KinomeScan data, we demonstrated simultaneous IRAK4 inhibition and verified superior in vivo efficacy compared to gilteritinib using the FLT3-ITD MOLM-13 cell line derived xenograft (CDX) murine model (Elgamal OA et al., ASH 2022). Given the curative potential of E2082-0047 in the immune competent model, ongoing efforts are focused on investigating the host immune response to AML. Given the safety and efficacy studies performed with E2082-0047 to date, a healthy volunteer study to best estimate dose for trials in AML is ongoing.
Preclinical
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FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
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FLT3-ITD mutation • FLT3 mutation • FLT3 F691L • FLT3-ITD F692L
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Xospata (gilteritinib)
over1year
Deciphering the mechanism of HM43239 inhibiting the mutant F691L resistant to gilteritinib in FMS-like tyrosine kinase 3. (PubMed, J Biomol Struct Dyn)
The F691L mutation had relatively larger effect on gilteritinib than HM43239, which showed as the changed and fixed conformation, respectively. These observations rationalized that the binding affinity of gilteritinib decreased more than that of HM43239 in the F691L mutant.Communicated by Ramaswamy H. Sarma.
Journal
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3 F691L
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Xospata (gilteritinib) • tuspetinib (HM43239)
over1year
Rational design of 4-((6-phenoxypyrimidin-4-yl)amino)-N-(4-(piperazin-1-yl)phenyl)-1H-pyrazole-3-carboxamide (LT-540-717) as orally bioavailable FLT3 inhibitor. (PubMed, Eur J Med Chem)
Herein, we describe the discovery of compound LT-540-717 (32), a potent FLT3 inhibitor (IC: 0.62 nM), starting from FN-1501...Furthermore, 32 showed an acceptable bioavailability (F = 33.3% in rat and 72.7% in beagles), a suitable half-life time (T = 3.5 h in rat and T = 11.1 h in beagles), and a satisfactory metabolic stability. In summary, these results show the therapeutic potential of 32 to become a new anti-AML drug, especially for AML harboring dual FLT3 (ITD, TKD) mutations.
Journal
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3-ITD mutation • FLT3 mutation • FLT3 D835Y • FLT3 F691L • FLT3 D835 • FLT3 D835V
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FN-1501
over1year
Discovery of PLM-102, a highly potent 3rd generation FLT3 inhibitor, in drug-resistant FLT3-ITD-TKD mutated acute myeloid leukemia (AACR 2023)
In FLT3-ITD-positive cell lines (MV4-11, MOLM-13, MOLM-14, Ba/F3-ITD-D835Y, Ba/F3-ITD-F691L), PLM-102 shows about 18~25-fold higher anti-proliferative activities than Gilteritinib. These results are very encouraging because large tumors have a limited blood supply and high interstitial fluid pressure, leading to a poor absorption of anticancer drugs. Pharmacokinetics of PLM-102 displayed higher bone-marrow exposure indicating better target engagement and benefits in the clinical translation in AML.In conclusion, PLM-102 is a promising therapeutic candidate for the FLT3-ITD-mutated AML as well as the acquired resistance to current FLT3 inhibitors.
PARP Biomarker
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FLT3 (Fms-related tyrosine kinase 3) • CASP3 (Caspase 3)
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FLT3-ITD mutation • FLT3 D835Y • FLT3 F691L • FLT3 D835
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Xospata (gilteritinib) • PLD-102
over1year
CTS2016, a novel AXL/FLT3 inhibitor for targeting AML/MDS and solid tumors (AACR 2023)
We tested CTS2016 as a single agent or in combination with either venetoclax, a Bcl-2 inhibitor, or azacitidine, a hypomethylating agent (HMA) and an epigenetic modulation drug, in a series of in vitro and in vivo studies using various AML models. CTS2016 resulted in a potent growth inhibitory effect with strong induction of cell death in a spectrum of AML cell lines carrying FLT3 mutations (FLT3-ITD and/or FLT3-TKD). CTS2016 orally administered once daily, demonstrated potent and dose-dependent antitumor responses in a variety of AML xenograft mouse models. These data demonstrate that CTS2016 could be a promising therapy for treating patients diagnosed with AML and MDS harboring FLT3 mutations and solid tumors such as NSCLC and TNBC with high-expression of AXL. More proof-of-concept data would come from the ongoing clinical trial.
IO biomarker
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FLT3 (Fms-related tyrosine kinase 3) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • AXL (AXL Receptor Tyrosine Kinase)
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FLT3-ITD mutation • FLT3 mutation • FLT3 F691L • AXL overexpression • FLT3 overexpression
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Venclexta (venetoclax) • azacitidine • CTS2016
almost2years
Resistance to a tyrosine kinase inhibitor mediated by changes to the conformation space of the kinase. (PubMed, Phys Chem Chem Phys)
Gilteritinib is a highly selective and effective inhibitor of the FLT3/ITD mutated protein, and is used successfully in treating acute myeloid leukaemia (AML)...Both mutants show a lower activation energy barrier which suggests that they are more likely to adopt an active state until inhibited, making the mutant enzymes more active. This suggests that a higher efficiency of tyrosine kinases contributes to resistance not only against type 2 but also against type 1 kinase inhibitors.
Journal
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FLT3 (Fms-related tyrosine kinase 3)
|
FLT3-ITD mutation • FLT3 F691L • FLT3 D698N
|
Xospata (gilteritinib)
almost2years
Sitravatinib as a potent FLT3 inhibitor can overcome gilteritinib resistance in acute myeloid leukemia. (PubMed, Biomark Res)
Our study reveals the potential therapeutic role of sitravatinib in FLT3 mutant AML and provides an alternative inhibitor for the treatment of AML patients who are resistant to current FLT3 inhibitors.
Journal
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FLT3 (Fms-related tyrosine kinase 3)
|
FLT3-ITD mutation • FLT3 mutation • FLT3 F691L • FLT3 expression • FLT3-ITD mutation + FLT3 F691L
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Xospata (gilteritinib) • sitravatinib (MGCD516)
almost2years
Design, synthesis, and evaluation of pyrido.[3,4-b]pyrazin-2(1H)-one derivatives as potent FLT3 inhibitors. (PubMed, Bioorg Med Chem)
Moreover, the treatment with compound 13 led to robust inhibition of FLT3 autophosphorylation on Tyr589/591 in MV4-11 cells. In summary, our data demonstrated that 13 was worthy of further study for the treatment of AML.
Journal
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3-ITD mutation • FLT3 D835Y • FLT3 F691L • FLT3 D835 • FLT3 D835V • FLT3 expression
2years
A Phase 1a/b Dose Escalation Study of the FLT3/BTK Inhibitor Luxeptinib (CG-806) in Patients with Relapsed or Refractory Acute Myeloid Leukemia (ASH 2022)
Luxeptinib suppresses additional signaling pathways in AML cells (CSF1R, PDGFRα, TRK, SYK, BTK, LYN, AKT, ERK, MAPK), kills primary AML cells insensitive to other FLT3 inhibitors at pM and low nM concentrations, and shows enhanced activity in combination with venetoclax...At 450 mg BID, one heavily pretreated AML patient (received 8 prior regimens including alloSCT and FLT3 inhibitors gilteritinib and crenolanib) had a 99% reduction in peripheral blasts (6.4x103/µL at C1D1 to 0.1x103/µL at C1D15), though the blast proportion increased during Cycle 2... As of July 8, 2022, luxeptinib is well tolerated at dose levels of 450, 600, 750, and 900 mg BID over multiple cycles without evidence of having reached the MTD. Luxeptinib in heavily pretreated relapsed FLT3-ITD AML patients has shown anti-tumor activity including a durable, MRD negative CR. Enrollment of patients with R/R AML is ongoing and updated clinical data with the G3 formulation will be presented at the meeting.
Clinical • P1 data
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FLT3 (Fms-related tyrosine kinase 3) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • LYN (LYN Proto-Oncogene Src Family Tyrosine Kinase) • SYK (Spleen tyrosine kinase) • CSF1R (Colony stimulating factor 1 receptor)
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FLT3 F691L
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Venclexta (venetoclax) • Xospata (gilteritinib) • crenolanib (ARO-002) • luxeptinib (CG-806)
2years
A Novel Inhibitor of FLT3 and Its Drug-Resistant Mutants with Superior Activity to Gilteritinib in Molm-13 Preclinical Acute Myeloid Leukemia Xenograft Model (ASH 2022)
Several FLT3 inhibitors have been developed such as the first generation multikinase inhibitor Midostaurin which is approved for newly diagnosed FLT3 mutant AML in combination with induction chemotherapy...Herein we describe 2082-0047, a novel tyrosine kinase inhibitor with sub-nanomolar potency against FLT3 mutant AML, including TKD mutations...Our non-GLP in vivo safety studies confirmed a broad therapeutic window of 2082-0047. Ongoing Investigational New Drug (IND) enabling studies will include comparing the effect of 2082-0047 to gilteritinib in an immunocompetent syngeneic AML murine model harboring both a Flt3-ITD and F691 TKD gatekeeper mutation.
Preclinical
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3-ITD mutation • FLT3 mutation • FLT3-TKD mutation • FLT3 D835Y • FLT3 F691L • FLT3 D835 • FLT3 D835V • FLT3 D835H
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Xospata (gilteritinib) • Rydapt (midostaurin)
2years
BCL-2 inhibitor synergizes with PI3Kδ inhibitor and overcomes FLT3 inhibitor resistance in acute myeloid leukaemia. (PubMed, Am J Cancer Res)
Furthermore, venetoclax combined with idelalisib led to tumour regression in all animals in this quizartinib-resistant AML model. Thus, these data indicate that combined inhibition of BCL-2 and PI3Kδ may be a promising strategy in AML, especially for patients with FLT3-ITD and/or FLT3-TKD mutations.
Journal • IO biomarker
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FLT3 (Fms-related tyrosine kinase 3) • PIK3CD (Phosphatidylinositol-4 5-Bisphosphate 3-Kinase Catalytic Subunit Delta)
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FLT3-ITD mutation • FLT3-TKD mutation • FLT3 F691L • MCL1 expression
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Venclexta (venetoclax) • Vanflyta (quizartinib) • Zydelig (idelalisib)
over2years
Rational polypharmacological targeting of FLT3, JAK2, ABL, and ERK1 suppresses the adaptive resistance to FLT3 inhibitors in AML. (PubMed, Blood Adv)
Pluripotin treatment curbed the progression of AML in multiple in vivo models including patient-derived primary AML cells in mouse xenotransplants. As a proof of concept, we demonstrate that targeted polypharmacological inhibition of key signaling nodes driving adaptive resistance can provide a durable response.
Journal
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FLT3 (Fms-related tyrosine kinase 3) • ABL1 (ABL proto-oncogene 1) • BCR (BCR Activator Of RhoGEF And GTPase) • JAK2 (Janus kinase 2)
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FLT3-ITD mutation • FLT3 F691L • FLT3 expression • FLT3-ITD expression
over2years
Understanding gilteritinib resistance to FLT3-F691L mutation through an integrated computational strategy. (PubMed, J Mol Model)
Moreover, the per-residue free energy decomposition suggested that the four residues (Phe803, Gly831, Leu832, and Ala833) located at the A-loop of FLT3 had a significant impact on the binding affinity of gilteritinib to the F691L mutant. This study may provide useful information for the design of novel FLT3 inhibitors specially targeting the F691L gatekeeper mutant.
Journal
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FLT3 (Fms-related tyrosine kinase 3)
|
FLT3 mutation • FLT3 F691L
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Xospata (gilteritinib)
over2years
Preclinical and pilot study of type I FLT3 tyrosine kinase inhibitor, crenolanib, with sorafenib in acute myeloid leukemia and FLT3-internal tandem duplication. (PubMed, Clin Cancer Res)
The combination of crenolanib and sorafenib was tolerable with antileukemic activities and rare emergence of FLT3-TKD mutations, which warrants further investigation.
Preclinical • Journal
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FLT3 (Fms-related tyrosine kinase 3) • STAT5A (Signal Transducer And Activator Of Transcription 5A)
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FLT3-ITD mutation • FLT3 mutation • FLT3-TKD mutation • FLT3 F691L
|
sorafenib • crenolanib (ARO-002)
over2years
Discovery of indirubin-3'-aminooxy-acetamide derivatives as potent and selective FLT3/D835Y mutant kinase inhibitors for acute myeloid leukemia. (PubMed, Eur J Med Chem)
The selectivity profiles of compound 13a in the oncology kinase panel and various human cancer cell lines were prominent, demonstrating that its inhibitory activities were mainly focused on a few members of the receptor tyrosine kinase family and AML versus solid tumor cell lines. Furthermore, significant in vivo anticancer efficacy of compound 13a was confirmed in a xenograft animal model implanted with FLT3-ITD/D835Y-expressing MOLM-14 cells related to secondary TKD mutation.
Journal
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3-ITD mutation • FLT3 mutation • FLT3 D835Y • FLT3 F691L • FLT3 D835
over2years
QUIZARTINIB WITH DECITABINE AND VENETOCLAX (TRIPLET) IS ACTIVE IN PATIENTS WITH FLT3-ITD MUTATED ACUTE MYELOID LEUKEMIA - A PHASE I/II STUDY (EHA 2022)
Of 23 pts with R/R AML (median 3 prior Rx, 78% with ≥1 prior FLT3i including prior gilteritinib in 70%, and 39% had a prior alloSCT), 78% achieved CRc (3 CR, 15 CRi) with 6/16 and 5/18 responders achieving FLT3-PCR and multicolor flow cytometry negativity, respectively. Interestingly, RAS/MAPK mutations but not emergent TKD mutations were associated with primary and secondary resistance to the triplet. Accrual continues and updated clinical, NGS and mass cytometry (CyTOF) data will be presented.
Clinical • P1/2 data
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3-ITD mutation • FLT3-TKD mutation • FLT3 F691L
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Venclexta (venetoclax) • Xospata (gilteritinib) • Vanflyta (quizartinib) • decitabine
over2years
MYELOID KINOME INHIBITOR HM43239 OVERCOMES ACQUIRED RESISTANCE IN ACUTE MYELOID LEUKEMIA MODELS (EHA 2022)
HM43239 inhibited FcγR-induced SYK and JAK/STAT5 activation in KG-1a (FLT3-WT) cells that upregulate RAS signaling which is a mechanism of acquired resistance to gilteritinib. Its ability to also inhibit SYK and, by reducing the activity of these upstream kinases, to also impair the activity of EKR1/2 and JAK/STAT5 that participate in rescue pathways, makes this a particularly interesting molecule with the potential of offsetting the development of resistance that is common with other FLT3 inhibitors. A Phase 1/2 trial of HM43239 in patients with AML is open and accruing patients (NCT03850574).
Preclinical
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FLT3 (Fms-related tyrosine kinase 3) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • JAK2 (Janus kinase 2) • JAK1 (Janus Kinase 1) • SYK (Spleen tyrosine kinase)
|
FLT3-ITD mutation • FLT3 mutation • FLT3 D835Y • FLT3 F691L • FLT3 D835 • FLT3 D835V • FLT3 D835H • FLT3 overexpression • FLT3 wild-type • FLT3-ITD mutation + FLT3 F691L
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Xospata (gilteritinib) • tuspetinib (HM43239)
over2years
The Irreversible FLT3 Inhibitor FF-10101 Is Active Against a Diversity of FLT3 Inhibitor Resistance Mechanisms. (PubMed, Mol Cancer Ther)
We also demonstrate that FF-10101 can potentially address resistance mechanisms associated with growth factors present in the bone marrow microenvironment but is vulnerable to mutation at C695, the amino acid required for covalent FLT3 binding. These data suggest that FF-10101 possesses a favorable resistance profile that may contribute to improved single-agent efficacy when used in patients with FLT3-mutant AML.
Journal
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FLT3 (Fms-related tyrosine kinase 3)
|
FLT3 mutation • FLT3 F691L • FLT3 D835
|
FF-10101
over2years
Molecular profile of FLT3-mutated relapsed/refractory AML patients in the phase 3 ADMIRAL study of gilteritinib. (PubMed, Blood Adv)
Acquisition of multiple Ras/MAPK pathway gene mutations at relapse suggests a high level of pathway reactivation is needed to overcome the gilteritinib treatment effect. These findings provide insight into the R/R AML molecular profile and the impact of FLT3 inhibitors on mutational evolution associated with treatment resistance and benefit of gilteritinib across a wide spectrum of molecular and genetic subgroups in FLT3-mutated R/R AML.
P3 data • Journal
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TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • WT1 (WT1 Transcription Factor)
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FLT3-ITD mutation • FLT3 mutation • NPM1 mutation • DNMT3A mutation • FLT3 F691L
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Xospata (gilteritinib)
over2years
Identification of 2-Aminopyrimidine Derivatives as FLT3 Kinase Inhibitors with High Selectivity over c-KIT. (PubMed, J Med Chem)
No clear myelosuppression was observed in the treated group of 36 in the MPO strain of zebrafish, even at 10 μM. In summary, our data demonstrated that 36 may represent a promising candidate for the treatment of FLT3 mutant AML.
Journal
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FLT3 (Fms-related tyrosine kinase 3) • KIT (KIT proto-oncogene, receptor tyrosine kinase)
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FLT3-ITD mutation • FLT3 mutation • FLT3 D835Y • FLT3 F691L • FLT3 D835 • FLT3 D835V • FLT3 expression • FLT3-ITD expression
3years
Rapid and Sensitive Diagnosis of Drug-Resistant FLT3-F691L Mutation by CRISPR Detection. (PubMed, Front Mol Biosci)
Confirmed by the tests on diluted plasmids and 120 AML patient samples, this method can achieve a sensitivity of 0.1% and complete the whole diagnosis process within 40 min. Potentially, this method will play an important role in point-of-care applications and guidance of AML treatment.
Journal
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3 F691L
3years
Clinical Significance of FLT3 Mutations in a Comprehensive NGS Multicenter Study of AML: HM-Screen-Japan 01 (ASH 2021)
This is the first report to analyze R/R and ND unfit AML cases in a Japanese cohort using F1H NGS, revealing a higher incidence of FLT3 -ITD/TKD mutations than previously reported. Therefore, F1H mutational analyses for R/R and ND unfit AML patients harboring FLT3 -ITD/TKD mutations may reveal novel therapeutic targets that are sensitive to FLT3i. Samples from these patients showed non-canonical gain-of-function mutations, such as N676K, S451F, V592D, and F691L, which could guide the selection of optimal anti-FLT3 therapies.
Clinical • Next-generation sequencing
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KRAS (KRAS proto-oncogene GTPase) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • WT1 (WT1 Transcription Factor)
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KRAS mutation • FLT3 mutation • NPM1 mutation • DNMT3A mutation • RUNX1 mutation • FLT3 F691L • FLT3 N676K
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FoundationOne® Heme CDx
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Xospata (gilteritinib) • Vanflyta (quizartinib)
3years
The FLT3 F691L Gatekeeper Mutation Promotes Clinical Resistance to Gilteritinib + Venetoclax (GILT + VEN) in AML (ASH 2021)
To test if FLT3 signaling was important for resistance, we exposed parental cells to higher concentrations of gilteritinib, which have been shown to partly overcome F691L, as well as the FLT3i FF-10101, which binds FLT3 at a different site and is not affected by the F691L mutation. We have developed a robust cell line model of early and late resistance to FLT3i that mimics the timing and expansion of resistance mutations in the clinic. Our model of early and late resistance to GILT combinations can prospectively predict mechanisms of resistance. Although uncommon as a mechanism of resistance to GILT monotherapy, our model and early patient data predicts that F691L mutations are more important for GILT + VEN resistance.
Clinical
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FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • FGF2 (Fibroblast Growth Factor 2)
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NRAS mutation • FLT3 mutation • FLT3 F691L
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Venclexta (venetoclax) • Xospata (gilteritinib) • FF-10101
3years
Combination Therapy of FLT3 Tyrosine Kinase Inhibitors and BH3 Mimetics Targeting Antiapoptotic MCL-1 Synergistically Eliminates FLT3-ITD Acute Myeloid Leukemia Cells in Vitro and In Vivo (ASH 2021)
We have recently shown for the first time that a novel MCL-1 inhibitor S63845 elicited synergistic activity with FLT3 inhibitors AC220, sorafenib and with a multi-kinase inhibitor midostaurin at nanomolar doses in pre-clinical in vitro models of FLT3-ITD AML, including cells resistant to venetoclax ( Skwarska A, et al...Mice were treated for 3 weeks with low doses of midostaurin (25 mg/kg/5 days per week) and with MIK665, structurally optimized version of S63845 Mcl-1 inhibitor with improved pharmacokinetics in mice ( Halilovic E, et al...The long-term effect of combination on mice survival is currently being tested and will be reported. Altogether, our results indicate that efficacy of FLT3-ITD inhibitors can be enhanced through combination with low doses BH3 mimetics targeting MCL-1 and provide a rationale for the clinical evaluation of such combinations in FLT3 mutant AML patients.
Preclinical • Combination therapy • PARP Biomarker • IO biomarker
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FLT3 (Fms-related tyrosine kinase 3) • CASP3 (Caspase 3)
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FLT3-ITD mutation • FLT3 mutation • FLT3 D835Y • FLT3 F691L • FLT3 D835 • MCL1 expression
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Venclexta (venetoclax) • sorafenib • Rydapt (midostaurin) • Vanflyta (quizartinib) • S63845 • MIK665
3years
A Phase-Ib/II Clinical Evaluation of Ponatinib in Combination with Azacitidine in FLT3-ITD and CBL-Mutant Acute Myeloid Leukemia (PON-AZA study) (ASH 2021)
Introduction Despite the advent of targeted therapy for FLT3 -mutated AML, unmet need still exists for patients unfit for intensive chemotherapy, with no evidence that overall survival (OS) can be improved by combining either venetoclax (Konopleva et al...Adaptive on-target gilteritinib resistance may be due to the FLT3 -F691L gatekeeper mutation, whereas off-target resistance may be due to loss-of-function variants in CBL , which encodes an E3 ubiquitin-protein ligase that negatively regulates FLT3 (McMahon et al , 2019)...Preliminary efficacy was observed in CBL -mutated patients. Further clinical investigation of this regimen is warranted in patients with FLT3- or CBL -mutant AML.
Clinical • P1/2 data • Combination therapy
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3-ITD mutation • FLT3 mutation • FLT3 F691L • CBL mutation
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Venclexta (venetoclax) • Iclusig (ponatinib) • Xospata (gilteritinib) • azacitidine
3years
A Phase 1a/b Dose Escalation Study of the Mutation Agnostic FLT3/BTK Inhibitor Luxeptinib (CG-806) in Patients with Relapsed or Refractory Acute Myeloid Leukemia (ASH 2021)
Luxeptinib simultaneously suppresses additional signaling pathways in AML cells (CSF1R, PDGFRα, TRK, SYK, BTK, LYN, AKT, ERK, MAPK), kills primary AML cells insensitive to other FLT3 inhibitors at pM and low nM concentrations, and shows enhanced activity in combination with venetoclax...One heavily pretreated AML patient (8 prior regimens including alloSCT and FLT3 inhibitors gilteritinib and crenolanib) had 99% reduction of blasts in peripheral blood (from 6.38x10 3 /µL at C1D1 to 0.09x10 3 /µL at C1D15), though the decrease in blasts reversed during Cycle 2...MRD-negative complete remission (CR) was confirmed in one FLT3-ITD AML patient (6 prior regimens including 2 alloSCT and FLT3 inhibitor sorafenib) at Cycle 5 of treatment evidenced by reduction of FLT3-ITD VAF and blasts in bone marrow to below limit of detection (LOD) of PCR-based FLT3-ITD assay and high-sensitivity flow cytometry (LOD < 0.1%), respectively... As of June 7, 2021, luxeptinib is well tolerated at dose levels of 450 and 600 mg BID over multiple cycles and escalated to 750 mg BID (Cohort 3). Pharmacodynamic studies documented inhibition of FLT3 signaling, and anti-leukemic activity has been observed in heavily pretreated relapsed FLT3-ITD AML patients as evidenced by significant reduction of FLT3-ITD VAF and blasts in bone marrow and / or peripheral blood. One FLT3-ITD AML patient has had confirmed MRD negative CR and continues treatment.
Clinical • P1 data
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TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • NPM1 (Nucleophosmin 1) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • SRSF2 (Serine and arginine rich splicing factor 2) • LYN (LYN Proto-Oncogene Src Family Tyrosine Kinase) • SYK (Spleen tyrosine kinase) • CSF1R (Colony stimulating factor 1 receptor) • GATA2 (GATA Binding Protein 2)
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TP53 mutation • FLT3-ITD mutation • FLT3 mutation • NPM1 mutation • ASXL1 mutation • TET2 mutation • FLT3 D835Y • FLT3 F691L • PTPN11 mutation • FLT3 D835 • SRSF2 mutation • GATA2 mutation • SRSF2 P95L
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Venclexta (venetoclax) • sorafenib • Xospata (gilteritinib) • crenolanib (ARO-002) • luxeptinib (CG-806)
over3years
Identification of Thieno[3,2-d]pyrimidine Derivatives as Dual Inhibitors of Focal Adhesion Kinase and FMS-like Tyrosine Kinase 3. (PubMed, J Med Chem)
Importantly, 26 is superior to PF-562271 in terms of apoptosis induction, anchorage-independent growth inhibition, and tumor burden reduction in the MDA-MB-231 xenograft mouse model...Finally, in an orthotopic mouse model using MDA-MB-231, 26 remarkably prevents metastasis of orthotopic tumors to lymph nodes. Taken together, the results indicate that 26 possesses potential therapeutic value against highly invasive cancers and relapsed AML.
Journal
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3 mutation • FLT3 F691L
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benzesulfonate (PF-562271)
over3years
A dual inhibitor overcomes drug-resistant FLT3-ITD acute myeloid leukemia. (PubMed, J Hematol Oncol)
KX2-391 exhibited potent growth inhibitory and apoptosis promoting effects on diverse AML cell lines harboring FLT3-ITD mutations and AC220-resistant mutations at the D835 and F691 residues in TKD and inhibited FLT3 phosphorylation and its downstream signaling targets. KX2-391 also significantly inhibited the growth of 4 primary AML cells expressing FLT3-ITD and 2 primary AML cells expressing FLT3-ITD-D835Y. Our preclinical data highlight KX2-391 as a promising FLT3 inhibitor for the treatment of AML patients harboring FLT3 mutations, especially refractory/relapsed patients with F691L and other FLT3-TKD mutations.
Journal
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3-ITD mutation • FLT3 mutation • FLT3-TKD mutation • FLT3 D835Y • FLT3 F691L • FLT3 D835 • FLT3 expression • FLT3-ITD expression
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Vanflyta (quizartinib) • tirbanibulin oral (KX2-391 oral)
over3years
[VIRTUAL] A PHASE 1A/B DOSE ESCALATION STUDY OF THE MUTATION AGNOSTIC FLT3/BTK INHIBITOR LUXEPTINIB (CG-806) IN PATIENTS WITH RELAPSED OR REFRACTORY ACUTE MYELOID LEUKEMIA (EHA 2021)
Luxeptinib simultaneously suppresses additional signaling pathways in AML cells (CSF1R, PDGFRα, TRK, SYK, BTK, LYN, AKT, ERK, MAPK), kills primary AML cells insensitive to other FLT3 inhibitors at pM and low nM concentrations, and shows enhanced activity in combination with venetoclax...One heavily pretreated patient with relapsed AML with mutated NPM1, DNMT3A, and FLT3-ITD who had previously progressed after chemotherapy, alloSCT, and two FLT3 inhibitors (gilteritinib, crenolanib) demonstrated clinical anti-leukemic activity with a decrease in peripheral blood blasts from 93% to 10% during Cycle 1...Pharmacodynamic studies documented inhibition of FLT3 signaling pathway, and anti-leukemic activity has been observed in the setting of AML relapsed following therapy with multiple prior FLT3 inhibitors. Enrollment of patients with R/R AML continues and updated clinical data from this dose escalation study will be presented at the meeting.
Clinical • P1 data
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TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • ASXL1 (ASXL Transcriptional Regulator 1) • LYN (LYN Proto-Oncogene Src Family Tyrosine Kinase) • SYK (Spleen tyrosine kinase) • CSF1R (Colony stimulating factor 1 receptor)
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TP53 mutation • FLT3-ITD mutation • NPM1 mutation • DNMT3A mutation • ASXL1 mutation • FLT3 D835Y • FLT3 F691L • FLT3 D835
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Venclexta (venetoclax) • Xospata (gilteritinib) • crenolanib (ARO-002) • luxeptinib (CG-806)
over3years
Combating drug resistance in acute myeloid leukaemia by drug rotations: the effects of quizartinib and pexidartinib. (PubMed, Cancer Cell Int)
AML patients are not likely to benefit from a quizartinib/pexidartinib rotation protocol. A combination of tyrosine kinase inhibitors (with different molecular targets) might be more useful in the future. Development of specific FLT3 inhibitors that are less sensitive to resistance mutations might also lead to a better outcome.
Journal
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3 F691L • FLT3 expression
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Vanflyta (quizartinib) • Turalio (pexidartinib)