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DRUG:

MIK665

i
Other names: MIK665, MIK-665, S64315, MIK 665, S 64315, S-64315, S064315
Associations
Company:
HitGen, Novartis, Servier
Drug class:
MCL1 inhibitor
Associations
5d
The tubulin polymerization inhibitor gambogenic acid induces myelodysplastic syndrome cell apoptosis through upregulation of Fas expression mediated by the NF-κB signaling pathway. (PubMed, Cancer Biol Ther)
GNA combined with the MCL-1 inhibitor MIK665 potently suppressed the proliferation of MDS cells...GNA-induced apoptosis was attenuated in either p65 KO or Fas KO cells. These results demonstrate that GNA inhibited tubulin polymerization and induced apoptosis of MDS cells through upregulation of Fas expression mediated by the NF-κB signaling pathway, suggesting a chemotherapeutic strategy for MDS by microtubule dynamics disruption.
Journal
|
CASP3 (Caspase 3) • CASP7 (Caspase 7)
|
MCL1 expression
|
MIK665
3ms
Trial termination • Combination therapy
|
MIK665 • S65487
6ms
Phase I/II Trial of S64315 Plus Azacitidine in Acute Myeloid Leukaemia (clinicaltrials.gov)
P1/2, N=17, Completed, Institut de Recherches Internationales Servier | Active, not recruiting --> Completed | Trial completion date: Mar 2024 --> Aug 2023 | Trial primary completion date: Mar 2024 --> Aug 2023
Trial completion • Trial completion date • Trial primary completion date • Combination therapy
|
azacitidine • MIK665
8ms
AMPK inhibition sensitizes acute leukemia cells to BH3 mimetic-induced cell death. (PubMed, Cell Death Differ)
BH3 mimetics, including the BCL2/BCLXL/BCLw inhibitor navitoclax and MCL1 inhibitors S64315 and tapotoclax, have undergone clinical testing for a variety of neoplasms...Building on the observation that BH3 mimetic monotherapy induces AMP kinase (AMPK) activation in multiple acute leukemia cell lines, we report that the AMPK inhibitors (AMPKis) dorsomorphin and BAY-3827 sensitize these cells to navitoclax or MCL1 inhibitors...Conversely, dorsomorphin synergizes with navitoclax or the MCL1 inhibitor S63845 to induce cell death in primary acute leukemia samples ex vivo and increases the antitumor effects of navitoclax or S63845 in several xenograft models in vivo with little or no increase in toxicity in normal tissues. These results suggest that AMPK inhibition can sensitize acute leukemia to multiple BH3 mimetics, potentially allowing administration of lower doses while inducing similar antineoplastic effects.
Journal • IO biomarker
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BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1) • BCL2L2 (BCL2 Like 2) • AMPK (Protein Kinase AMP-Activated Catalytic Subunit Alpha 1)
|
navitoclax (ABT 263) • S63845 • tapotoclax (AMG 176) • dorsomorphin (Compound C) • BAY-3827 • MIK665
8ms
MCL1 inhibition targets Myeloid Derived Suppressors Cells, promotes antitumor immunity and enhances the efficacy of immune checkpoint blockade. (PubMed, Cell Death Dis)
In this study, we show that the MCL1 inhibitor S64315 reduces melanoma tumor growth in an immune cell-dependent manner in mice...Together, this proof-of-concept study demonstrates the potential of combining an MCL1 inhibitor with anti-PD-1 in the treatment of melanoma. It justifies the further development of next generation MCL1 inhibitors to improve efficacy of ICIs in treating malignant melanoma.
Journal • Checkpoint inhibition • PD(L)-1 Biomarker • IO biomarker • Checkpoint block
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BCL2 (B-cell CLL/lymphoma 2) • CD8 (cluster of differentiation 8)
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MCL1 expression
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MIK665
10ms
Trial primary completion date • Combination therapy
|
MIK665 • S65487
1year
Dual targeting of Mcl-1 and Bcl-2 to overcome chemoresistance in cervical and colon cancer. (PubMed, Anticancer Drugs)
This combination also prolonged overall survival compared with using S64315 or venetoclax alone. Our research highlights the therapeutic potential of inhibiting Mcl-1 and Bcl-2 simultaneously in chemoresistant cancers and provides a rationale for initiating clinical trials to investigate the combination of S64315 and venetoclax for the treatment of advanced colon and cervical cancer.
Journal
|
BCL2 (B-cell CLL/lymphoma 2)
|
Venclexta (venetoclax) • MIK665
1year
Trial completion date • Combination therapy
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MIK665 • S65487
over1year
Simultaneous Inhibition of Mcl-1 and Bcl-2 Induces Synergistic Cell Death in Hepatocellular Carcinoma. (PubMed, Biomedicines)
Therefore, we analyzed the efficacy of the two BH3-mimetics ABT-199 (Bcl-2 inhibitor) and MIK665 (Mcl-1 inhibitor) in HCC cell lines with differential expression levels of endogenous Bcl-2 and Mcl-1. Both drugs acted synergistically, highlighting the effectivity of this specific BH3-mimetic combination, particularly in HCC cell lines. These results indicate the potential of combining inhibitors of the BCL-2 family as new therapeutic options in HCC.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2)
|
BCL2 expression • MCL1 expression
|
Venclexta (venetoclax) • MIK665
over1year
VOB560-MIK665 Combination First in Human Trial in Patients With Hematological Malignancies (Relapsed/Refractory Non-Hodgkin Lymphoma, Relapsed/Refractory Acute Myeloid Leukemia, or Relapsed/Refractory Multiple Myeloma) (clinicaltrials.gov)
P1, N=37, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Sep 2024 --> Dec 2023 | Trial primary completion date: Sep 2024 --> Dec 2023
Trial completion date • Trial primary completion date • Combination therapy
|
MIK665 • S65487
over1year
Design of rigid protein-protein interaction inhibitors enables targeting of undruggable Mcl-1. (PubMed, Proc Natl Acad Sci U S A)
Despite being previously considered undruggable, seven small-molecule Mcl-1 inhibitors have recently entered clinical trials. Here, we report the crystal structure of the clinical-stage inhibitor AMG-176 bound to Mcl-1 and analyze its interaction along with clinical inhibitors AZD5991 and S64315...Nuclear Magnetic Resonance (NMR)-based free ligand conformer analysis demonstrates that such unprecedented induced fit is uniquely achieved by designing highly rigid inhibitors, preorganized in their bioactive conformation. By elucidating key chemistry design principles, this work provides a roadmap for targeting the largely untapped PPI class more successfully.
Journal
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BCL2 (B-cell CLL/lymphoma 2)
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AZD5991 • tapotoclax (AMG 176) • MIK665 • murizatoclax (AMG 397)
over1year
The Role of BCL-2 and PD-1/PD-L1 Pathway in Pathogenesis of Myelodysplastic Syndromes. (PubMed, Int J Mol Sci)
The challenge is the observed resistance to venetoclax, for which the MCL-1 protein may be largely responsible. Molecules with the potential to break the associated resistance include S63845, S64315, chidamide and arsenic trioxide (ATO)...Knockdown of the PD-L1 gene in preclinical studies was associated with increased levels of BCL-2 and MCL-1 in lymphocytes T, which could increase their survival and promote tumor apoptosis. A trial (NCT03969446) is currently underway to combine inhibitors from both groups.
Review • Journal
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BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1)
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Venclexta (venetoclax) • Epidaza (chidamide) • S63845 • arsenic trioxide • MIK665
over1year
Venetoclax and dinaciclib elicit synergisticpreclinicalefficacy against high-risk B-cell leukemia (AACR 2023)
In summary, our study identified a highly synergistic drug combination, venetoclax and dinaciclib, for the treatment of hypodiploid B ALL, an aggressive leukemia with few effective current therapies. Finally, the promising results presented in this study may prompt further studies to support the inclusion of hypodiploid and other B-ALL patients to clinical trials combining phase I/II drugs against BCL-2 (mainly venetoclax) and CDK9 (dinaciclib, alvocidib, flavopiridol, SNS-032) or MCL-1 (MIK-665).
IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • CDK9 (Cyclin Dependent Kinase 9)
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Venclexta (venetoclax) • alvocidib (DSP-2033) • SNS-032 • dinaciclib (MK-7965) • MIK665
2years
NEW THERAPEUTICAL APPROACH FOR HEPATOCELLULAR CARCINOMA: INHIBITION OF BCL-2 AND MCL-1 (AASLD 2022)
The human HCC cell lines HepG2, Hep3B and Huh7 were treated with 0,01 - 5 μM ABT-199 and 0,01 - 6 μM MIK665 either alone or in combination. HCC is one of the most common cancer types and the third leading cause of cancer related deaths worldwide. Although screening and therapy have improved over the past years, overall prognosis remains poor. Therefore, new therapeutic options are urgently needed.
IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • CASP9 (Caspase 9) • CASP7 (Caspase 7) • ANXA5 (Annexin A5)
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BAX expression
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Venclexta (venetoclax) • MIK665
2years
NA1-115-7, from Zygogynum pancheri, is a new selective MCL-1 inhibitor inducing the apoptosis of hematological cancer cells but non-toxic to normal blood cells or cardiomyocytes. (PubMed, Biomed Pharmacother)
Synthetic inhibitors targeting these proteins have been developed, and some hematological malignancies are now widely treated with a BCL-2 inhibitor (venetoclax)...Six MCL-1 inhibitors (S64315, AZD-5991, AMG-176, AMG-397, ABBV-467 and PRT1419) have been evaluated in clinical trials since 2016, but some were affected by safety issues and none are currently used clinically...Importantly, a similar treatment with NA1-115-7 was not toxic to erythrocytes, peripheral blood mononuclear cells, platelets, or cardiomyocytes. These results highlight the potential of natural products for use as specific BH3 mimetics non-toxic to normal cells, and they suggest that NA1-115-7 may be a promising tool for use in cancer treatment.
Journal • IO biomarker
|
BCL2L1 (BCL2-like 1)
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MCL1 expression
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Venclexta (venetoclax) • AZD5991 • tapotoclax (AMG 176) • PRT1419 • ABBV-467 • MIK665 • murizatoclax (AMG 397)
over2years
INHIBITION OF BCL-2 AND MCL-1 EFFECTIVELY INDUCES CELL DEATH IN HEPATOCELLULAR CARCINOMA (HCC) CELL LINES (UEGW 2022)
BH3-mimetics directly target resistance to apoptosis as one of the hallmarks of cancer. They have already proven beneficial in hematologic and some solid cancers. We now provide evidence that a combination of the BH3-mimetics ABT-199 and MIK665 effectively induces cell death in HCC cell lines.
Preclinical
|
BCL2 (B-cell CLL/lymphoma 2) • CASP3 (Caspase 3) • CASP7 (Caspase 7) • ANXA5 (Annexin A5)
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Venclexta (venetoclax) • MIK665
over2years
THE COMBINATION VENETOCLAX PLUS MCL1 OVERCOMES DRUG RESISTANCE IN ACUTE PROMYELOCYTIC LEUKEMIA (EHA 2022)
Methods Primary leukemic blasts from APL mice (n=4) and patients (age, 25-52y; n=10) were treated with VEN (250-500nM), ATO, ATRA (1µM), and S64315 (10-50nM) monotherapies and combinations and evaluated for cell survival. Finally, in vivo CLDX model revealed limited effect of VEN and S64315 monotherapy, while the combination was able to effectively reduce the leukemic burden, resulting in increased overall survival (vehicle:15 vs Combo:42 days). Conclusion The combination of BCL2 and MCL1 inhibition is a potential effective treatment in ATO/RA resistant APL patients and could be clinically explored in this category of patients with very poor prognosis.
IO biomarker
|
MCL1 (Myeloid cell leukemia 1) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C)
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BCL2 expression • MCL1 expression
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Venclexta (venetoclax) • Vesanoid (tretinoin) • MIK665
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
over3years
Unmasking BCL-2 Addiction in Synovial Sarcoma by Overcoming Low NOXA. (PubMed, Cancers (Basel))
Importantly, the venetoclax/S63845 combination induced tumor regressions in SS patient-derived xenograft (PDX) models. As a very close analog of S63845 (S64315) is now in clinical trials with venetoclax in AML (NCT03672695), the combination of MCL-1 BH3 mimetics and venetoclax should be considered for SS patients as a new therapy.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • SS18 (SS18 Subunit Of BAF Chromatin Remodeling Complex)
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BCL2 expression • SS18-SSX fusion
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Venclexta (venetoclax) • S63845 • MIK665
over3years
[VIRTUAL] RUXOLITINIB COMBINED WITH THE MCL-1 INHIBITOR S63845 IS HIGHLY EFFICIENT IN TREATING MYELOMA IN THE INA-6 XENOGRAFT MODEL (EMN 2021)
Both, the very similar Mcl-1 inhibitor MIK665 (S64315) and the JAK1/2 inhibitor ruxolitinib are currently in early clinical evaluation in patients with advanced multiple myeloma. The data presented here suggest that a combination of ruxolitinib and the Mcl-1 inhibitor S63845 is particularly efficient in control of multiple myeloma.
Preclinical
|
BCL2 (B-cell CLL/lymphoma 2) • IL6 (Interleukin 6) • BCL2L1 (BCL2-like 1)
|
Jakafi (ruxolitinib) • S63845 • MIK665
over3years
[VIRTUAL] Identification of S65487/VOB560 as a potent and selective intravenous 2nd-generation BCL-2 inhibitor active in wild-type and clinical mutants resistant to Venetoclax (AACR 2021)
Strong and persistent tumor regression in xenograft models of lymphoid malignancies in mouse and rat were observed at well tolerated doses following weekly IV administration of S65487 in combination with the MCL-1-specific inhibitor, S64315/MIK665. Altogether, these data demonstrate that S65487/VOB560 has significant therapeutic potential against human lymphoid and myeloid malignancies as well as in patients with Venetoclax resistant leukemias. Clinical studies are currently ongoing with S65487/VOB560 (NCT03755154).
Clinical • IO biomarker
|
BCL2L1 (BCL2-like 1)
|
BCL2 mutation • BCL2 G101V
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Venclexta (venetoclax) • Bcl-2 Family Inhibitors • MIK665 • S65487
almost4years
[VIRTUAL] The high expression of pro-apoptotic BCL2 family members in uveal melanomas contribute to their sensitivity to MCL1 inhibitors (SID 2021)
In hematological cancers, venetoclax (BCL2 inhibitor) is approved and S64315 (MCL1 inhibitor/MCL1i) is in clinical trials. However, MCL1i alone was ineffective at killing the UM stem-like cells, but a combination with venetoclax synergistically killed UM stem-like cells, inhibited their capacity to self-renew, and reduced tumor growth in vivo (p<0.01). In summary, our data indicated MCL1i, alone or in combination with venetoclax, are promising treatments for UM.
IO biomarker
|
BRAF (B-raf proto-oncogene) • BCL2 (B-cell CLL/lymphoma 2) • CASP3 (Caspase 3) • CASP7 (Caspase 7)
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BRAF mutation • BRAF V600 • BCL2 expression
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Venclexta (venetoclax) • MIK665
4years
Discovery of S64315, a Potent and Selective Mcl-1 Inhibitor. (PubMed, J Med Chem)
During optimization, we have also established predictive PD markers of Mcl-1 inhibition and achieved both efficient in vitro cell killing and tumor regression in Mcl-1 dependent cancer models. The preclinical candidate has drug-like properties that have enabled its development and entry into clinical trials.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2)
|
MIK665
over4years
Simultaneously Inhibiting BCL2 and MCL1 Is a Therapeutic Option for Patients with Advanced Melanoma. (PubMed, Cancers (Basel))
We explored the efficacy of combining two BH3 mimetics, ABT-199 and a myeloid cell leukemia sequence 1 (MCL1) inhibitor (S63845 or S64315/MIK665) in cutaneous, mucosal and acral melanomas, in vitro and in vivo. Our knockdown/knockout experiments suggest that several pro-apoptotic BCL2 family members, BCL2-like 11 (apoptosis facilitator) (BIM), phorbol-12-myristate-13-acetate-induced protein 1 (NOXA) or BID, play a role in the combination-induced effects. Overall, our study supports the rationale for combining an MCL1 inhibitor with a BCL2 inhibitor as a therapeutic option in patients with advanced melanoma.
Clinical • Journal
|
BRAF (B-raf proto-oncogene) • BCL2 (B-cell CLL/lymphoma 2) • PMAIP1 (Phorbol-12-Myristate-13-Acetate-Induced Protein 1)
|
BRAF V600E
|
Venclexta (venetoclax) • S63845 • MIK665
over4years
[VIRTUAL] The effective killing of the difficult-to-treat melanomas with the combinations of MCL1 inhibitors S63845/MIK665 plus Navitoclax (SID 2020)
Moreover, in mouse xenograft model, the combination inhibited tumor growth of multiple melanomas (p <0.01), had tolerable toxicity, and reduced sphere forming capacity (p < 0.05) in a downstream in vitro assay. In summary, this study suggests that dual targeting of MCL1 and BCLXL can be an alternative treatment for melanoma patients who have exhausted current treatment options.
IO biomarker
|
BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1)
|
BRAF mutation • NF1 mutation
|
navitoclax (ABT 263) • S63845 • MIK665
over4years
Structure-Guided Discovery of a Selective Mcl-1 Inhibitor with Cellular Activity. (PubMed, J Med Chem)
The obtained compounds described here exhibit nanomolar binding affinity and mechanism-based cellular efficacy, caspase induction, and growth inhibition. These early research efforts illustrate drug discovery optimization from thienopyrimidine hits to a lead compound, the chemical series leading to the identification of our more advanced compounds S63845 and S64315.
Journal
|
BCL2 (B-cell CLL/lymphoma 2)
|
S63845 • MIK665
over4years
MCL1 inhibitors S63845/MIK665 plus Navitoclax synergistically kill difficult-to-treat melanoma cells. (PubMed, Cell Death Dis)
Recapitulated in our mouse xenograft model, the combination inhibited tumor growth, reduced sphere-forming capacity (p  0.40). Taken together, this study suggests that dual targeting of MCL1 and BCLXL should be considered as a treatment option for difficult-to-treat melanoma patients.
Journal
|
BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1)
|
navitoclax (ABT 263) • S63845 • MIK665