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Ref Type Journal Article
PMID (27760111)
Authors Kotschy A, Szlavik Z, Murray J, Davidson J, Maragno AL, Le Toumelin-Braizat G, Chanrion M, Kelly GL, Gong JN, Moujalled DM, Bruno A, Csekei M, Paczal A, Szabo ZB, Sipos S, Radics G, Proszenyak A, Balint B, Ondi L, Blasko G, Robertson A, Surgenor A, Dokurno P, Chen I, Matassova N, Smith J, Pedder C, Graham C, Studeny A, Lysiak-Auvity G, Girard AM, Grave F, Segal D, Riffkin CD, Pomilio G, Galbraith LC, Aubrey BJ, Brennan MS, Herold MJ, Chang C, Guasconi G, Cauquil N, Melchiore F, Guigal-Stephan N, Lockhart B, Colland F, Hickman JA, Roberts AW, Huang DC, Wei AH, Strasser A, Lessene G, Geneste O
Title The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models.
Journal Nature
Vol 538
Issue 7626
Date 2016 Oct 19
URL
Abstract Text Avoidance of apoptosis is critical for the development and sustained growth of tumours. The pro-survival protein myeloid cell leukemia 1 (MCL1) is overexpressed in many cancers, but the development of small molecules targeting this protein that are amenable for clinical testing has been challenging. Here we describe S63845, a small molecule that specifically binds with high affinity to the BH3-binding groove of MCL1. Our mechanistic studies demonstrate that S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway. In vivo, S63845 shows potent anti-tumour activity with an acceptable safety margin as a single agent in several cancers. Moreover, MCL1 inhibition, either alone or in combination with other anti-cancer drugs, proved effective against several solid cancer-derived cell lines. These results point towards MCL1 as a target for the treatment of a wide range of tumours.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
S63845 S63845 3 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
S63845 MIK655 MCL1 Inhibitor 14 S63845 (MIK655) is a small molecule binds to and inhibits Mcl1, leading to apoptosis in tumor cells (PMID: 27760111, PMID: 32513939).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF mutant melanoma sensitive S63845 + Trametinib Preclinical - Cell culture Actionable In a preclinical study, combination of S63845 and Mekinist (trametinib) resulted in potent cytotoxic effects in BRAF-mutated melanoma cells in culture compared to the cytostatic effect of Mekinist (trametinib) alone (PMID: 27760111). 27760111
NRAS mutant melanoma sensitive S63845 + Trametinib Preclinical - Cell culture Actionable In a preclinical study, combination of S63845 and Mekinist (trametinib) resulted in potent cytotoxic effects in NRAS-mutated melanoma cells in culture compared to the cytostatic effect of Mekinist (trametinib) alone (PMID: 27760111). 27760111
ERBB2 amp breast cancer sensitive Lapatinib + S63845 Preclinical - Cell culture Actionable In a preclinical study, the combination of S63845 and Tykerb (lapatinib) resulted in potent cytotoxic effects in ERBB2 (HER2)-amplified breast cancer cells in culture compared to the cytostatic effect of Tykerb (lapatinib) alone (PMID: 27760111). 27760111
Unknown unknown lymphoma not applicable S63845 Preclinical - Cell culture Actionable In a preclinical study, S63845 inhibited survival of several lymphoma cell lines in culture (PMID: 27760111). 27760111
BRAF mutant melanoma sensitive S63845 + Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, combination of S63845 and Zelboraf (vemurafenib) resulted in potent cytotoxic effects in BRAF-mutated melanoma cells in culture compared to the cytostatic effect of Zelboraf (vemurafenib) alone (PMID: 27760111). 27760111