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DRUG CLASS:

Aurora kinase inhibitor

24d
Molecular simulations and machine learning methods for the identification of novel aurora A kinase inhibitors. (PubMed, J Biomol Struct Dyn)
Both docking studies revealed perfect binding of all identified ligands in active site pockets of AAK protein with similar amino acids of active sites as compared with standard BindingDB_50433632 compound and co-crystal ligand VX-680 binding mode of AAK protein. Therefore, it can be concluded that computational drug discovery approaches are meticulously implemented to identify potential AAKs inhibitors/modulators, and credential of the work was substantiated through the identification of three potential AAKs inhibitors/modulators that may hold significant promise for improving cancer management, however, need extensive biological assays or pre-clinical trials for assessing the efficacy profile of the identified compounds.
Journal • Machine learning
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AURKA (Aurora kinase A)
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tozasertib (MK-0457)
27d
Recent advancements in mechanistic research, therapeutic potential, and structure-activity relationships of aurora kinase inhibitors in cancer therapies. (PubMed, Bioorg Chem)
Similarly, compounds 28, 16, and 7 demonstrate strong AURK-B inhibitory activity, with IC50 values of 10.5 nM, 12 nM, and 14.09 nM, respectively. This comprehensive overview aims to support medicinal chemists in developing more potent, selective, and safe AURK inhibitors as potential anticancer therapeutics.
Review • Journal
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BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • PLK1 (Polo Like Kinase 1) • KIF2C (Kinesin Family Member 2C)
2ms
Establishment and validation of the prognostic risk model based on the anoikis-related genes in esophageal squamous cell carcinoma. (PubMed, Ann Med)
The IC50 values of predicted drugs, in the case of Tozasertib 1096 and WIKI4 1940, were significantly variant between risk groups...The study established an ARG prognosis model of ESCC. It provided a reference for the research of ARGs in ESCC.
Journal
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LAMC2 (Laminin subunit gamma 2) • TNFSF10 (TNF Superfamily Member 10)
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tozasertib (MK-0457)
2ms
Differential regulation of expression of the protein kinases DYRK1A and DYRK1B in cancer cells. (PubMed, Sci Rep)
Consistently, AURK inhibitors VX-680 (tozasertib), MLN8237 (alisertib), AZD1152-HQPA (barasertib) resulted in the upregulation of DYRK1B expression in A549 cells. In summary, our findings indicate that the expression of DYRK1A and DYRK1B is differentially regulated in cancer cells and reveal that the kinase inhibitor XMU-MP-1 increases DYRK1B expression likely through off target inhibition of Aurora kinases.
Journal
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AURKA (Aurora kinase A) • AURKB (Aurora Kinase B) • DYRK1A (Dual Specificity Tyrosine Phosphorylation Regulated Kinase 1A) • DYRK1B (Dual Specificity Tyrosine Phosphorylation Regulated Kinase 1B)
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alisertib (MLN8237) • barasertib-HQPA (AZD2811) • tozasertib (MK-0457)
5ms
The construction of a prognostic model by apoptosis-related genes to predict survival, immune landscape, and medication in cholangiocarcinoma. (PubMed, Clin Res Hepatol Gastroenterol)
Our project suggested that the prognostic model with apoptotic features can effectively predict prognosis in CCA patients, proffering prognostic biomarkers and potential therapeutic targets for CCA patients.
Journal
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MAP3K1 (Mitogen-Activated Protein Kinase Kinase Kinase 1)
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Estybon (rigosertib) • AMG 900
6ms
Drug-induced senescence by aurora kinase inhibitors attenuates innate immune response of macrophages on gastric cancer organoids. (PubMed, Cancer Lett)
It was found that DGCs showed drug-induced senescent phenotype after treatment by aurora kinases inhibitors (AURKi) Barasertib-HQPA and Danusertib. The up-regulation of local MCP-1/CCL2 can interact with MCP-1/CCL2 receptor (CCR2) expressed on macrophages and suppress their innate immunity to cancer cells. Overall, the special response of DGC to AURKi suggests that clinicians should select a sequential therapy with senescent cell clearance after AURKi treatment for DGC.
Journal
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CCL2 (Chemokine (C-C motif) ligand 2) • CCR2 (C-C Motif Chemokine Receptor 2)
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barasertib-HQPA (AZD2811) • danusertib (PHA-739358)
8ms
Combination of an aurora kinase inhibitor and the ABL tyrosine kinase inhibitor asciminib against ABL inhibitor-resistant CML cells. (PubMed, Med Oncol)
It also evaluated the efficacy of the ABL TKI asciminib and the aurora kinase inhibitor LY3295668. Combining asciminib and aurora kinase inhibition enhanced the efficacy and is proposed as a new therapeutic option for patients with CML. These findings have clinical implications for a potential novel therapeutic strategy for CML patients.
Journal
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ABL1 (ABL proto-oncogene 1) • AURKA (Aurora kinase A) • AURKB (Aurora Kinase B)
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Scemblix (asciminib) • LY3295668
9ms
The effects of Aurora Kinase inhibition on thyroid cancer growth and sensitivity to MAPK-directed therapies. (PubMed, Cancer Biol Ther)
We further demonstrated that combined MEK1/2 and AURKB inhibition slowed cell growth, which was phenocopied by inhibiting AURKB and ERK1/2. Finally, we show that combined AURKB and ERK1/2 inhibition induces apoptosis in BRAF-mutant thyroid cancer cell lines, together suggesting a potential combination therapy for BRAF-mutant thyroid cancer patients.
Journal
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AURKB (Aurora Kinase B)
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BRAF mutation
9ms
Suppression of NSCLC progression via the co-administration of Danusertib, an AURK inhibitor, and KRIBB11, an HSF1 inhibitor. (PubMed, Biochem Pharmacol)
Furthermore, the combination treatment inhibits tumor growth and AKT signaling in the xenograft mouse model, increases levels of the tumor tissue oxidation product malondialdehyde (MDA), and induces DNA damage. To summarize, a potential therapeutic approach for NSCLC may involve dual inhibition of AURK and HSF1, resulting in the downregulation of the PI3K/AKT signaling pathway, and the activation of ROS-mediated mitochondrial and DNA damage pathways.
Journal
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BCL2 (B-cell CLL/lymphoma 2) • CASP3 (Caspase 3) • CDK1 (Cyclin-dependent kinase 1) • CCNB1 (Cyclin B1) • HSF1 (Heat Shock Transcription Factor 1)
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danusertib (PHA-739358)
9ms
A comprehensive review on role of Aurora kinase inhibitors (AKIs) in cancer therapeutics. (PubMed, Int J Biol Macromol)
The drawbacks of existing inhibitors like selectivity, drug resistance and toxicity have also been addressed. Since, majority of inhibitors are Aurora kinase inhibitor (AKI) type-1 that bind to the active (DFGin and Cin) conformation of the kinase, this information may be utilized to design highly selective kinase inhibitors that can be combined with other therapeutic agents for better clinical outcomes.
Review • Journal
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AURKA (Aurora kinase A) • AURKB (Aurora Kinase B)
11ms
Tozasertib activates anti-tumor immunity through decreasing regulatory T cells in melanoma. (PubMed, Neoplasia)
Single-cell analysis revealed that AURKB suppressed anti-tumor immunity by increasing MIF-CD74/CXCR4 signaling between tumor cells and lymphocytes. Our study suggests that AURKB is a newly identified anti-tumor immunity suppressor, whose inhibitors may be developed as novel anti-tumor immunity drugs and may have synergistic anti-melanoma effects with immune checkpoint therapies.
Journal
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CD8 (cluster of differentiation 8) • CD74 (CD74 Molecule) • CD4 (CD4 Molecule) • AURKB (Aurora Kinase B)
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tozasertib (MK-0457)
1year
The Aurora kinase inhibitor AT9283 inhibits Burkitt lymphoma growth by regulating Warburg effect. (PubMed, PeerJ)
The reversal of the Warburg effect in BL cells and the subsequent inhibition of cell proliferation and induction of apoptosis were observed by targeting Aurora A and Aurora B with AT9283. This finding may present new therapeutic options and targets for BL.
Journal
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MYC (V-myc avian myelocytomatosis viral oncogene homolog) • LDHA (Lactate dehydrogenase A) • HIF1A (Hypoxia inducible factor 1, alpha subunit) • HK2 (Hexokinase 2) • PKM (Pyruvate Kinase M1/2)
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HIF1A expression
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AT9283
1year
EP0042, a Dual FLT3 and Aurora Kinase Inhibitor: Results from an Ongoing Phase I/IIa Dose-Finding/Dose Optimization Study in Patients with Relapsed/Refractory Acute Myeloid Leukemia (ASH 2023)
12 patients received a prior FLT3 inhibitor including midostaurin, gilteritinib or sorafenib and 8/12 patients received ≥2 prior FLT3 inhibitors. Dose optimisation cohorts are continuing to identify the RP2D. Further cohorts are planned for evaluation of EP0042 in combination with standard of care therapies.
Clinical • P1/2 data
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3-ITD mutation • FLT3 mutation • FLT3 wild-type
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sorafenib • Xospata (gilteritinib) • Rydapt (midostaurin) • EP0042
1year
High in vitro and in vivo activity of BI-847325, a dual MEK/Aurora kinase inhibitor, in human solid and hematologic cancer models. (PubMed, Cancer Res Commun)
BI-847325 showed a broader range of activity than the MEK inhibitor GDC-0623. In conclusion, dual MEK/Aurora kinase inhibition shows remarkable potential for treating multiple types of hematological and solid tumors. The combination with capecitabine was synergistic in colorectal, gastric, and mammary cancer.
Preclinical • Journal
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BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • MAP2K1 (Mitogen-activated protein kinase kinase 1)
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BRAF mutation • NRAS mutation
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capecitabine • BI 847325 • GDC-0623
over1year
High spindle and kinetochore-associated complex subunit-3 expression predicts poor prognosis and correlates with adverse immune infiltration in hepatocellular carcinoma. (PubMed, World J Gastrointest Surg)
High SKA3 expression led to poor prognosis in patients with HCC by enhancing HCC proliferation and repressing immune cell infiltration surrounding HCC. SKA3 may be used as a biomarker for poor prognosis and as a therapeutic target in HCC.
Journal
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CD8 (cluster of differentiation 8)
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gemcitabine • sorafenib • paclitaxel • sunitinib • doxorubicin hydrochloride • tozasertib (MK-0457)
over1year
Phase II Study of Ilorasertib (ABT348) in Patients With CDKN2A Deficient Solid Tumors (clinicaltrials.gov)
P2, N=12, Terminated, M.D. Anderson Cancer Center | Completed --> Terminated; Study terminated due to company's decision to discontinue drug development
Trial termination • Pan tumor • Metastases
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CDKN2A (Cyclin Dependent Kinase Inhibitor 2A)
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CDKN2A deletion • CDKN2A mutation
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ilorasertib (ABT348)
over1year
Discovery of a first-in-class Aurora A covalent inhibitor for the treatment of triple negative breast cancer. (PubMed, Eur J Med Chem)
11c displayed comparable therapeutic efficacy in an MDA-MB-231 xenograft mouse model relative to the positive control ENMD-2076, while requiring only half the dose of ENMD-2076. These results confirmed that 11c may be a promising drug candidate for the treatment of triple negative breast cancer (TNBC). Our work may provide a new perspective on the design of covalent inhibitors of Aurora kinase.
Journal
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AURKA (Aurora kinase A)
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ENMD-2076
over1year
Enrollment closed • Combination therapy • Metastases
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EGFR mutation • EGFR L858R • EGFR exon 19 deletion • EGFR T790M
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Tagrisso (osimertinib) • LY3295668
over1year
The inhibition of Aurora A kinase regulates phospholipid remodeling by upregulating LPCAT1 in glioblastoma. (PubMed, Neoplasma)
Notably, the inhibition of Aurora A kinase by shRNA knockdown and treatment with Aurora A kinase inhibitors such as Alisertib, AMG900, or AT9283 upregulated LPCAT1 mRNA and protein expression in vitro. Aurora A kinase inhibition increased LPCAT1 expression and suppressed GBM cell proliferation. The combination of Aurora kinase inhibition with LPCAT1 inhibition may exert promising synergistic effects on GBM.
Journal
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AURKA (Aurora kinase A) • LPCAT1 (Lysophosphatidylcholine Acyltransferase 1)
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alisertib (MLN8237) • AMG 900 • AT9283
over1year
AURKA Identified as Potential Lung Cancer Marker through Comprehensive Bioinformatic Analysis and Experimental Verification. (PubMed, Crit Rev Eukaryot Gene Expr)
The CCK-8 assay was used to determine the IC50 of the AURKA inhibitor CCT137690 in H1993 cells...AURKA, BIRC5, CCNB1, DLGAP5, KIF11, and KIF15 may be critical genes that influence the occurrence, development, and prognosis of NSCLC. AURKA significantly affects the proliferation and migration of lung cancer cells by disrupting the cell cycle.
Journal
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BIRC5 (Baculoviral IAP repeat containing 5) • AURKA (Aurora kinase A) • KIF11 (Kinesin Family Member 11) • CCNB1 (Cyclin B1)
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CCT137690
over1year
Overexpression of TREM1 is Associated with the Immune-Suppressive Microenvironment and Unfavorable Prognosis in Pan-Cancer. (PubMed, J Inflamm Res)
Through connective map analysis, therapeutically potential compounds like tozasertib and TPCA-1 were identified, which can be used synergistically with immunotherapy to improve the poor prognosis of patients with high TREM1 levels. Through a systematic and comprehensive pan-cancer analysis, we demonstrated that overexpression of TREM1 in tumors correlated closely with unfavorable outcome, infiltration of immune-suppressive cells, and immune regulation, which highlights its potential use as a tumor prognostic biomarker and a novel target for immunotherapy.
Journal • IO biomarker • Pan tumor
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CD8 (cluster of differentiation 8)
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tozasertib (MK-0457)
almost2years
Comprehensive genomics analysis of aging related gene signature to predict the prognosis and drug resistance of colon adenocarcinoma. (PubMed, Front Pharmacol)
Low risk patients were more sensitive to small molecule drugs including Erlotinib, Sunitinib, MG-132, CGP-082996, AZ628, Sorafenib, VX-680, and Z-LLNle-CHO. Four risk genes (CALB1, CPA3, NOXA1, and TNNT1) had significant positive correlation with their methylation level, while six genes (CCL22, GPRC5B, HSPA1A, MFNG, PABPC1L, and PCOLCE2) were negatively correlated with their methylation level. This study provides novel understanding of heterogeneity in COAD from the perspective of senescence, and develops signatures for prognosis prediction in COAD.
Journal • Tumor mutational burden • Gene Signature • IO biomarker
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TMB (Tumor Mutational Burden) • CCL2 (Chemokine (C-C motif) ligand 2) • CALB1 (Calbindin 1) • CCL22 (C-C Motif Chemokine Ligand 22) • CPA3 (Carboxypeptidase A3) • HSPA1A (Heat Shock Protein Family A (Hsp70) Member 1A) • PABPC1L (Poly(A) Binding Protein Cytoplasmic 1 Like)
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erlotinib • sorafenib • sunitinib • AZ 628 • MG132 • tozasertib (MK-0457)
almost2years
Preclinical evaluation of immunomodulatory effects of aurora kinase inhibition in HPV+ cancers (AACR 2023)
We tested the in vivo efficacy of alisertib, an Aurora Kinase A inhibitor, in an immunocompetent mouse model (mEER) for HPV+ oropharyngeal cancers...Our proposed research will have a positive impact because we will gain insight into the immune responses underlying the co-dependency of HPV+ cancers on Aurora kinase. Our research may lead to an increase in the rates of long-term, durable clinical responses or may allow for therapy de-escalation.
Preclinical • Immunomodulating
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CD8 (cluster of differentiation 8) • AURKA (Aurora kinase A) • CD4 (CD4 Molecule) • HMGB1 (High Mobility Group Box 1) • CALR (Calreticulin) • FOXP3 (Forkhead Box P3) • ANXA5 (Annexin A5)
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CD8 expression
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alisertib (MLN8237)
almost2years
Phenotypic profiling of Aurora inhibitors using the OncoPanelTMplatform (AACR 2023)
Activity of the AurA-selective inhibitor, MLN8054, was also evaluated in the Eurofins Discovery BioMAP® Diversity PLUS human primary cell phenotypic profiling service to give a broader view of its biological activity. These studies demonstrate the combined value of using the OncoPanel and BioMAP platforms to determine mechanistic, functional, and broader biological activity of therapeutic candidates in relevant cellular models for a better translational understanding of potential therapeutic capabilities and accelerate decision-making.
CASP3 (Caspase 3)
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OncoPanel™ Assay
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MLN8054
almost2years
Luxeptinib interferes with LYN-mediated activation of SYK and modulates BCR signaling in lymphoma. (PubMed, PLoS One)
This study sought to refine understanding of how LUX modulates the earliest steps downstream of the BCR following its activation by anti-IgM in lymphoma cells in comparison to ibrutinib (IB). These results indicate that LUX is targeting autophosphorylation of LYN or a step further upstream of LYN in the cascade of signal generated by BCR and that it does so more effectively than IB. The fact that LUX has activity at or upstream of LYN is important because LYN is an essential signaling intermediate in multiple cellular signaling processes that regulate growth, differentiation, apoptosis, immunoregulation, migration and EMT in normal and cancer cells.
Journal
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FLT3 (Fms-related tyrosine kinase 3) • LYN (LYN Proto-Oncogene Src Family Tyrosine Kinase) • SYK (Spleen tyrosine kinase) • NLRP3 (NLR Family Pyrin Domain Containing 3) • BLNK (B Cell Linker)
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Imbruvica (ibrutinib) • luxeptinib (CG-806)
almost2years
Combined inhibition of Aurora Kinases and Bcl-xL induces apoptosis through select BH3-only proteins. (PubMed, J Biol Chem)
We demonstrate that combination of a Bcl-2 homology (BH)3-mimetic inhibitor (ABT-737), a selective inhibitor of Bcl-xL, Bcl-2, and Bcl-w, with alisertib or danusertib potently induces apoptosis through the Bcl-2 family effector protein Bax. On the other hand, we found Alisertib treatment causes activation of caspase-2, which promotes apoptosis by cleaving Bid into tBid, a suppressor of both Bcl-xL and Mcl-1. Together, these results define the Bcl-2 protein network critically involved in AURK inhibitor-induced apoptosis, and suggest that BH3-mimetics targeting Bcl-xL may help overcome resistance to AURK inhibitors in cancer cells.
Journal
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BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1) • BCL2L2 (BCL2 Like 2)
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alisertib (MLN8237) • ABT-737 • danusertib (PHA-739358)
almost2years
Chasing the Epigenetic Landscape to Prevent CD19 Antigen Escape (EHA-EBMT-CART 2023)
To restore CD19 surface levels, CD19-negative cells were treated with azacytidine for 48 hours in vitro and the mice were injected with azacytidine once per day for 2 weeks to confirm CD19 recovery in vivo... Our findings showed how the epigenetic landscape down-regulates the CD19 expression, which often leads to antigen escape in relapsed conditions. It also opened the possibility of using a combinational approach (by targeting epigenetic regulators) to enhance CART-cell activity by preventing/restoring CD19 antigen escape. In addition, further experiments are ongoing to investigate how CD19 activation through CAR-T cells triggers epigenetic regulation and the role of Aurora kinases in this process.
IO biomarker
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CD19 (CD19 Molecule)
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CD19 expression
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azacitidine
2years
BI-847325, a selective dual MEK and Aurora kinases inhibitor, reduces aggressive behavior of anaplastic thyroid carcinoma on an in vitro three-dimensional culture. (PubMed, Cancer Cell Int)
The results of the present study suggest that BI-857,325 might be an effective multi-targeted anticancer drug for ATC treatment.
Preclinical • Journal
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ABCB1 (ATP Binding Cassette Subfamily B Member 1) • AURKA (Aurora kinase A) • AURKB (Aurora Kinase B) • ANXA5 (Annexin A5)
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VEGFA expression
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BI 847325
2years
2-Phenoxy-3, 4'-bipyridine derivatives inhibit AURKB-dependent mitotic processes by disrupting its localization. (PubMed, Eur J Med Chem)
Hierarchical clustering of cell fitness profiles reveals that these compounds cluster with each other, rather than with known AURK inhibitors such as AMG900 and VX-680. The discovery and optimization of compounds that disrupt AURKB localization are successfully facilitated by MIPS. Our findings suggest that 2-phenoxy-3, 4'-bipyridine derivatives have the potential to be further developed as effective therapeutics for the treatment of malignancy by delocalizing AURKB.
Journal
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AURKB (Aurora Kinase B)
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AMG 900 • tozasertib (MK-0457)
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)
|
FLT3 F691L
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Venclexta (venetoclax) • Xospata (gilteritinib) • crenolanib (ARO-002) • luxeptinib (CG-806)
2years
EP0042, a Dual FLT3 and Aurora Kinase Inhibitor: Preliminary Results of an Ongoing Phase I/IIa First in Human Study in Patients with Relapsed/Refractory Acute Myeloid Leukemia (ASH 2022)
EP0042 has resulted in inhibition of tumor growth in FLT3-ITD and FLT3-ITD-TKD human tumor xenograft models and in quizartinib-resistant primary AML samples (Moore A et al...5 pts received a prior FLT3 inhibitor including midostaurin, gilteritinib or sorafenib...The dose escalation is continuing at intermittent and continuous dosing to establish the MTD and optimal RP2D dose for further evaluation. Once a RP2D is confirmed, a single arm dose expansion is planned in FLT3 mutated and wild type R/R AML, and the combination of EP0042 with other agents will be explored.
Clinical • P1/2 data
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FLT3 (Fms-related tyrosine kinase 3) • AURKB (Aurora Kinase B)
|
FLT3 mutation • FLT3 wild-type
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sorafenib • Xospata (gilteritinib) • Rydapt (midostaurin) • Vanflyta (quizartinib) • EP0042
2years
A Phase 1a/b Dose Escalation Study of the BTK/FLT3 Inhibitor Luxeptinib in Patients with Relapsed or Refractory B-Cell Malignancies (ASH 2022)
Luxeptinib kills malignant B-cells insensitive to ibrutinib or venetoclax with concentrations in the nanomolar range and shows enhanced activity in combination with venetoclax. Luxeptinib has a favorable safety profile in patients treated with 150 mg to 900 mg BID over multiple cycles. Antitumor activity was observed in multiple B-NHL subtypes and CLL/SLL patients post ibrutinib relapse. Enrollment of additional patients at dose level 6 (900 mg) is ongoing while the more bioavailable G3 formulation is being explored.
Clinical • P1 data
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FLT3 (Fms-related tyrosine kinase 3) • SYK (Spleen tyrosine kinase)
|
Venclexta (venetoclax) • Imbruvica (ibrutinib) • luxeptinib (CG-806)
2years
Aurora Kinase B/C Inhibitor GSK1070916 Specifically Targets Juvenile Myelomonocytic Leukemia Cells with SHP2(PTPN11) Mutation (ASH 2022)
The colony-forming ability of primary JMML cells was completely inhibited under treatment of GSK1070916 (500 nM). In conclusion, aurora kinase B can be used as a promising therapeutic target for SHP2-mutant JMML patients, and the aurora kinase B/C inhibitor GSK1070916 could be a candidate for the treatment of JMML.
PARP Biomarker
|
BCL2L1 (BCL2-like 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • AURKA (Aurora kinase A) • CASP3 (Caspase 3) • AURKB (Aurora Kinase B)
|
PTPN11 mutation
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NMI-900
2years
Pan-Aurora Kinase Inhibitor Danusertib Induces Apoptosis of Epstein-Barr Virus-transformed B-Cells Through Caspase and Endoplasmic Reticulum Stress Signaling. (PubMed, Anticancer Res)
Danusertib treatment led to apoptosis of EBV-transformed B-cells through ER stress-associated proteins and mitochondrial caspase activation. These results suggest that aurora kinases may be valuable targets for potential therapeutic agents against EBV-associated carcinoma.
Journal
|
AURKA (Aurora kinase A)
|
danusertib (PHA-739358)
2years
Combined TRIP13 and Aurora kinase inhibition induces apoptosis in human papillomavirus-driven cancers. (PubMed, Clin Cancer Res)
Our data support a model in which HPV-positive cancer cells maintain a balance of MAD2L1 and TRIP13 to allow mitotic exit and survival in the absence of RB. Because it does not affect cells with intact RB function, this novel combination may have a wide therapeutic window, enabling the effective treatment of RB-deficient cancers.
Journal
|
TRIP13 (Thyroid Hormone Receptor Interactor 13) • BUB1B (BUB1 Mitotic Checkpoint Serine/Threonine Kinase B) • MAD2L1 (Mitotic Arrest Deficient 2 Like 1)
2years
Journal
|
HER-2 (Human epidermal growth factor receptor 2) • CSF2 (Colony stimulating factor 2)
|
CCT137690
2years
Concomitant targeting of FLT3 and BTK overcomes FLT3 inhibitor resistance in acute myeloid leukemia through inhibition of autophagy. (PubMed, Haematologica)
CG-806 further significantly reduced AML burden and extended survival in an in vivo PDX leukemia murine model of FLT3 inhibitorresistant FLT3-ITD/TKD double mutant primary AML. Taken together, CG-806 exerts a unique mechanistic action and pre-clinical activity, suggesting further development in FLT3 wild-type and mutant AML.
Journal
|
FLT3 (Fms-related tyrosine kinase 3) • BTK (Bruton Tyrosine Kinase)
|
FLT3-ITD mutation • FLT3 mutation • FLT3 wild-type
|
luxeptinib (CG-806)
2years
Bioinformatics and network-based screening and discovery of potential molecular targets and small molecular drugs for breast cancer. (PubMed, Front Pharmacol)
Finally, we proposed 16 candidate repurposing drugs YM201636, masitinib, SB590885, GSK1070916, GSK2126458, ZSTK474, dasatinib, fedratinib, dabrafenib, methotrexate, trametinib, tubastatin A, BIX02189, CP466722, afatinib, and belinostat for BC through molecular docking analysis. Using BC cell lines, we validated that masitinib inhibits the mTOR signaling pathway and induces apoptotic cell death. Therefore, the proposed results might play an effective role in the treatment of BC patients.
Journal
|
EGFR (Epidermal growth factor receptor) • TOP2A (DNA topoisomerase 2-alpha) • BIRC5 (Baculoviral IAP repeat containing 5) • AURKA (Aurora kinase A) • SOX2 • MIR34A (MicroRNA 34a-5p) • TP63 (Tumor protein 63) • CDK1 (Cyclin-dependent kinase 1) • MIR16 (MicroRNA 16) • MIR23b (MicroRNA 23b) • KDM5B (Lysine Demethylase 5B)
|
Mekinist (trametinib) • Gilotrif (afatinib) • dasatinib • Tafinlar (dabrafenib) • methotrexate • omipalisib (GSK2126458) • Beleodaq (belinostat) • Inrebic (fedratinib) • NMI-900 • OP-11 • SB-590885 • Kinaction (masitinib)
2years
AML-377 A "Designed" High-Throughput Drug Screening Strategy Identifies Aurora Kinase A Inhibitors as Promising Preclinical Candidates for the Treatment of NPM1-Mutated AML. (PubMed, Clin Lymphoma Myeloma Leuk)
We demonstrated that using HTS can considerably shorten drug discovery time scales, leading to the identification of promising lead compounds. Our study is the first to provide preclinical evidence of the antileukemic activity of AURKAi, with particular focus on NPM1-mutated AML.
Preclinical • Journal
|
NPM1 (Nucleophosmin 1) • AURKA (Aurora kinase A)
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NPM1 mutation
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alisertib (MLN8237) • ENMD-2076 • MK-5108 • MK-8745
over2years
A “Designed” High-Throughput Drug Screening Strategy Identifi es Aurora Kinase A Inhibitors as Promising Preclinical Candidates for the Treatment of NPM1-Mutated AML (SOHO 2022)
In the validation assay, 2 compounds (MK-5108 and MK-8745) were confi rmed as more active against NPM1-mutated than NPM1–wild-type AML cells by either CyQUANT or apoptosis assay. Strikingly, we confi rmed selectivity for two additional AURKAi (Alisertib and ENMD-2076, both isoform-selective inhibitors of AURKA) that were not included in the screening library... We demonstrated that using HTS can considerably shorten drug discovery time scales, leading to the identifi cation of promising lead compounds. Our study is the fi rst to provide preclinical evidence of the antileukemic activity of AURKAi, with particular focus on NPM1-mutated AML.
Preclinical
|
NPM1 (Nucleophosmin 1) • AURKA (Aurora kinase A)
|
NPM1 mutation
|
alisertib (MLN8237) • ENMD-2076 • MK-5108 • MK-8745
over2years
Extended Abstract: New BTKi (SOHO 2022)
It has also been studied in combination with idelalisib or entospletinib in CLL and other B-cell lymphomas though without clear benefi t for the combinations over monotherapy16,17. Tirabrutinib is approved in Japan for WM, lymphoplasmacytic lymphoma (LPL), and RRPCNSL, and in South Korea for RR-PCNSL18. TG-1701 is a selective covalent BTKi that has been studied as a monotherapy and in combination with ublituximab and umbralisib with preliminary results suggesting both effi cacy and manageable safety19. Orelabrutinib, another selective covalent BTKi, has been studied as a monotherapy in CLL in addition to other B-cell malignancies, also with favorable safety and effi cacy20,21 and it is approved in China for rel/ref CLL and MCL22. Finally, DTRMWXHS-12 is a covalent BTKi that uniquely is being studied in combination with everolimus and pomalidomide (triplet referred to as DTRM-555), given that this combination was determined to lead to synthetic lethality in both in vivo and in vitro screening studies, with safety and activity seen in early studies23,24...This resistance mechanism appears shared among available irreversible BTK inhibitors including ibrutinib, acalabrutinib and zanubrutinib26...Three such inhibitors have completed phase 1 studies in CLL: vecabrutinib, nemtabrutinib, and pirtobrutinib with another currently in phase 1, luxeptinib...Subsequently, pirtobrutinib is being further studied as both a monotherapy and in combination with venetoclax-rituximab in phase 3 trials in both the frontline and relapsed/refractory settings in CLL in addition to MCL...These non-C481 BTK mutations conferred resistance across multiple non-covalent BTKi’s (in addition to pirtobrutinib, vecabrutinib, nemtabrutinib and fenebrutinib were tested) in addition to variable levels of resistance to covalent BTKi’s36...This is being accomplished by improved tolerability, allowing for patients to stay on drug for longer, and potentially improved effi cacy, including activity despite acquisition of C481 resistance mutations, in the case of the non-covalent inhibitors. The non-covalent inhibitors would help fi ll a major area of unmet need for CLL patients progressing on covalent BTK inhibitors who are not candidates for or progress following venetoclax therapy.
IO biomarker
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FLT3 (Fms-related tyrosine kinase 3) • PLCG2 (Phospholipase C Gamma 2) • IL2 (Interleukin 2) • ITK (IL2 Inducible T Cell Kinase)
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Chr del(11q) • BTK C481S • PLCG2 mutation • BTK mutation • BTK C481
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Venclexta (venetoclax) • Imbruvica (ibrutinib) • Rituxan (rituximab) • Brukinsa (zanubrutinib) • Calquence (acalabrutinib) • Zydelig (idelalisib) • Inokai (orelabrutinib) • entospletinib (GS-9973) • pomalidomide • Jaypirca (pirtobrutinib) • Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy) • edralbrutinib (TG-1701) • luxeptinib (CG-806) • vecabrutinib (SNS-062) • DTRM-555 • DTRMWXHS-12 • Velexbru (tirabrutinib) • fenebrutinib (RG7845) • nemtabrutinib (MK-1026)