The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models

Nature

Volumn 538, Issue 7626, 2016, Pages 477-482

  Kotschy, András ^a   Szlavik, Zoltán ^a   Murray, James ^b   Davidson, James ^b   Maragno, Ana Leticia ^c   Le Toumelin Braizat, Gaëtane ^c   Chanrion, Maïa ^c   Kelly, Gemma L ^d,e   Gong, Jia Nan ^d,e   Moujalled, Donia M ^f   Bruno, Alain ^c   Csekei, Márton ^a   Paczal, Attila ^a   Szabo, Zoltán B ^a   Sipos, Szabolcs ^a   Radics, Gábor ^a   Proszenyak, Agnes ^a   Balint, Balázs ^a   Ondi, Levente ^a   Blasko, Gábor ^a   Robertson, Alan ^b   Surgenor, Allan ^b   Dokurno, Pawel ^b   Chen, Ijen ^b   Matassova, Natalia ^b   Smith, Julia ^b   Pedder, Christopher ^b   Graham, Christopher ^a   Studeny, Aurélie ^c   Lysiak Auvity, Gaëlle ^c   Girard, Anne Marie ^c   Gravé, Fabienne ^c   Segal, David ^d,e   Riffkin, Chris D ^d,e   Pomilio, Giovanna ^f   Galbraith, Laura C A ^d,e   Aubrey, Brandon J ^d,e,g   Brennan, Margs S ^d,e   Herold, Marco J ^d,e   Chang, Catherine ^d,e   Guasconi, Ghislaine ^c   Cauquil, Nicolas ^c   Melchiore, Fabien ^c   Guigal Stephan, Nolwen ^c   Lockhart, Brian ^c   Colland, Frédéric ^c   Hickman, John A ^c   Roberts, Andrew W ^d,e,g   Huang, David C S ^d,e   Wei, Andrew H ^f,h   Strasser, Andreas ^d,e   Lessene, Guillaume ^d,e   Geneste, Olivier ^c   more..

^a Servier Research Institute of Medicinal Chemistry   (Hungary)

^b Vernalis PLC   (United Kingdom)

^c INSTITUT DE RECHERCHES SERVIER   (France)

^d WALTER AND ELIZA HALL INSTITUTE OF MEDICAL RESEARCH   (Australia)

^e UNIVERSITY OF MELBOURNE   (Australia)

^f MONASH UNIVERSITY   (Australia)

^g ROYAL MELBOURNE HOSPITAL   (Australia)

^h ALFRED HOSPITAL   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

A 1210477; ANTINEOPLASTIC AGENT; BENZYLOXYCARBONYLLEUCYLLEUCYLLEUCINAL; ERLOTINIB; IDARUBICIN; LAPATINIB; PROTEIN BAX; PROTEIN INHIBITOR; PROTEIN MCL 1; S 63845; TRAMETENIB; UNCLASSIFIED DRUG; VEMURAFENIB; VENETOCLAX; BAK1 PROTEIN, HUMAN; MCL1 PROTEIN, HUMAN; PROTEIN BAK; PYRIMIDINE DERIVATIVE; S63845; THIOPHENE DERIVATIVE;

APOPTOSIS; CANCER; CELLS AND CELL COMPONENTS; GENE EXPRESSION; INHIBITOR; PROTEIN; TUMOR;

ANIMAL MODEL; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ARTICLE; DRUG EFFICACY; DRUG MECHANISM; DRUG POTENCY; DRUG SELECTIVITY; DRUG TARGETING; DRUG TOLERABILITY; HEMATOLOGIC MALIGNANCY; HUMAN; HUMAN CELL; IN VITRO STUDY; LEUKEMIA; LYMPHOMA; MITOCHONDRION; MOUSE; MULTIPLE MYELOMA; NONHUMAN; PRIORITY JOURNAL; THERAPEUTIC INDEX; ANIMAL; ANTAGONISTS AND INHIBITORS; BIOLOGICAL MODEL; CHEMISTRY; DRUG EFFECTS; DRUG SCREENING; FEMALE; MALE; METABOLISM; MOLECULAR MODEL; NEOPLASMS; PATHOLOGY; TUMOR CELL LINE;

ANIMALS; ANTINEOPLASTIC AGENTS; APOPTOSIS; BCL-2 HOMOLOGOUS ANTAGONIST-KILLER PROTEIN; BCL-2-ASSOCIATED X PROTEIN; CELL LINE, TUMOR; FEMALE; HUMANS; LEUKEMIA; LYMPHOMA; MALE; MICE; MODELS, BIOLOGICAL; MODELS, MOLECULAR; MULTIPLE MYELOMA; MYELOID CELL LEUKEMIA SEQUENCE 1 PROTEIN; NEOPLASMS; PYRIMIDINES; THIOPHENES; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84993984528     PISSN: 00280836     EISSN: 14764687     Source Type: Journal    
DOI: 10.1038/nature19830     Document Type: Article

References (51)

1. Green, D. R. & Llambi, F. Cell death signaling. Cold Spring Harb. Perspect. Biol. 7, 1-24 (2015).
2. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646-674 (2011).
3. Czabotar, P. E., Lessene, G., Strasser, A. & Adams, J. M. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat. Rev. Mol. Cell Biol. 15, 49-63 (2014).
4. Petros, A. M. et al. Rationale for Bcl-xL/Bad peptide complex formation from structure, mutagenesis, and biophysical studies. Protein Sci. 9, 2528-2534 (2000).
5. Delbridge, A. R. D., Grabow, S., Strasser, A. & Vaux, D. L. Thirty years of BCL-2: translating cell death discoveries into novel cancer therapies. Nat. Rev. Cancer 16, 99-109 (2016).
6. Wilson, W. H. et al. Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity. Lancet Oncol. 11, 1149-1159 (2010).
7. Roberts, A. W. et al. Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. J. Clin. Oncol. 30, 488-496 (2012).
8. Roberts, A. W. et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 374, 311-322 (2016).
9. Juin, P., Geneste, O., Gautier, F., Depil, S. & Campone, M. Decoding and unlocking the BCL-2 dependency of cancer cells. Nat. Rev. Cancer 13, 455-465 (2013).
10. Beroukhim, R. et al. The landscape of somatic copy-number alteration across human cancers. Nature 463, 899-905 (2010).
11. Akgul, C. Mcl-1 is a potential therapeutic target in multiple types of cancer. Cell. Mol. Life Sci. 66, 1326-1336 (2009).
12. Glaser, S. P. et al. Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemia. Genes Dev. 26, 120-125 (2012).
13. Kelly, G. L. et al. Targeting of MCL-1 kills MYC-driven mouse and human lymphomas even when they bear mutations in p53. Genes Dev. 28, 58-70 (2014).
14. Koss, B. et al. Requirement for antiapoptotic MCL-1 in the survival of BCR-ABL B-lineage acute lymphoblastic leukemia. Blood 122, 1587-1598 (2013).
15. Grabow, S., Delbridge, A. R., Valente, L. J. & Strasser, A. MCL-1 but not BCL-XL is critical for the development and sustained expansion of thymic lymphoma in p53-deficient mice. Blood 124, 3939-3946 (2014).
16. Spinner, S. et al. Re-activation of mitochondrial apoptosis inhibits T-cell lymphoma survival and treatment resistance. Leukemia 30, 1520-1530 (2016).
17. Gong, J.-N. et al. Hierarchy for targeting pro-survival BCL2 family proteins in multiple myeloma: pivotal role of MCL1. Blood blood-2016-03-704908 (2016).
18. Wei, G. et al. Chemical genomics identifies small-molecule MCL1 repressors and BCL-XL as a predictor of MCL1 dependency. Cancer Cell 21, 547-562 (2012).
19. Leverson, J. D. et al. Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263 (navitoclax). Cell Death Dis. 6, e1590 (2015).
20. Pelz, N. F. et al. Discovery of 2-indole-acylsulfonamide myeloid cell leukemia 1 (Mcl-1) inhibitors using fragment-based methods. J. Med. Chem. 59, 2054-2066 (2016).
21. Nhu, D., Lessene, G., Huang, D. & Burns, C. J. Small molecules targeting Mcl-1: the search for a silver bullet in cancer therapy. MedChemComm 7, 778-787 (2016).
22. Opferman, J. T. et al. Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells. Science 307, 1101-1104 (2005).
23. Wang, X. et al. Deletion of MCL-1 causes lethal cardiac failure and mitochondrial dysfunction. Genes Dev. 27, 1351-1364 (2013).
24. Thomas, R. L. et al. Loss of MCL-1 leads to impaired autophagy and rapid development of heart failure. Genes Dev. 27, 1365-1377 (2013).
25. Lessene, G., Czabotar, P. E. & Colman, P. M. BCL-2 family antagonists for cancer therapy. Nat. Rev. Drug Discov. 7, 989-1000 (2008).
26. Bruncko, M. et al. Structure-guided design of a series of MCL-1 inhibitors with high affinity and selectivity. J. Med. Chem. 58, 2180-2194 (2015).
27. Tunquist, B. J., Woessner, R. D. & Walker, D. H. Mcl-1 stability determines mitotic cell fate of human multiple myeloma tumor cells treated with the kinesin spindle protein inhibitor ARRY-520. Mol. Cancer Ther. 9, 2046-2056 (2010).
28. Oltersdorf, T. et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435, 677-681 (2005).
29. Souers, A. J. et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat. Med. 19, 202-208 (2013).
30. Aubrey, B. J. et al. An inducible lentiviral guide RNA platform enables the identification of tumor-essential genes and tumor-promoting mutations in vivo. Cell Reports 10, 1422-1432 (2015).
31. Derenne, S. et al. Antisense strategy shows that Mcl-1 rather than Bcl-2 or Bcl-x(L) is an essential survival protein of human myeloma cells. Blood 100, 194-199 (2002).
32. Zhang, B., Gojo, I. & Fenton, R. G. Myeloid cell factor-1 is a critical survival factor for multiple myeloma. Blood 99, 1885-1893 (2002).
33. Lee, E. F. et al. A novel BH3 ligand that selectively targets Mcl-1 reveals that apoptosis can proceed without Mcl-1 degradation. J. Cell Biol. 180, 341-355 (2008).
34. Chen, L. et al. Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol. Cell 17, 393-403 (2005).
35. Touzeau, C. et al. The Bcl-2 specific BH3 mimetic ABT-199: a promising targeted therapy for t(11;14) multiple myeloma. Leukemia 28, 210-212 (2014).
36. Lazareth, A. et al. MB4-2 breakpoint in MMSET combined with del(17p) defines a subset of t(4;14) multiple myeloma with very poor prognosis. Haematologica 100, e471-e474 (2015).
37. Zhang, H. et al. Mcl-1 is critical for survival in a subgroup of non-small-cell lung cancer cell lines. Oncogene 30, 1963-1968 (2011).
38. Xiao, Y. et al. MCL-1 Is a key determinant of breast cancer cell survival: validation of MCL-1 dependency utilizing a highly selective small molecule inhibitor. Mol. Cancer Ther. 14, 1837-1847 (2015).
39. Cragg, M. S., Harris, C., Strasser, A. & Scott, C. L. Unleashing the power of inhibitors of oncogenic kinases through BH3 mimetics. Nat. Rev. Cancer 9, 321-326 (2009).
40. Cragg, M. S. et al. Treatment of B-RAF mutant human tumor cells with a MEK inhibitor requires Bim and is enhanced by a BH3 mimetic. J. Clin. Invest. 118, 3651-3659 (2008).
41. Corcoran, R. B. et al. Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS mutant cancer models. Cancer Cell 23, 121-128 (2013).
42. Perciavalle, R. M. et al. Anti-apoptotic MCL-1 localizes to the mitochondrial matrix and couples mitochondrial fusion to respiration. Nat. Cell Biol. 14, 575-583 (2012).
43. Fang, C. et al. Single diastereomer of a macrolactam core binds specifically to myeloid cell leukemia 1 (MCL1). ACS Med. Chem. Lett. 5, 1308-1312 (2014).
44. Moon, A. F., Mueller, G. A., Zhong, X. & Pedersen, L. C. A synergistic approach to protein crystallization: combination of a fixed-arm carrier with surface entropy reduction. Protein Sci. 19, 901-913 (2010).
45. Kabsch, W. XDS. Acta Crystallogr. D Biol. Crystallogr. 66, 125-132 (2010).
46. Vagin, A. & Teplyakov, A. MOLREP: an automated program for molecular replacement. J. Appl. Cryst. 30, 1022-1025 (1997).
47. Murshudov, G. N., Vagin, A. A. & Dodson, E. J. Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr. D Biol. Crystallogr. 53, 240-255 (1997).
48. Nikolovska-Coleska, Z. et al. Development and optimization of a binding assay for the XIAP BIR3 domain using fluorescence polarization. Anal. Biochem. 332, 261-273 (2004).
49. Murray, J. B., Roughley, S. D., Matassova, N. & Brough, P. A. Off-rate screening (ORS) by surface plasmon resonance. An efficient method to kinetically sample hit to lead chemical space from unpurified reaction products. J. Med. Chem. 57, 2845-2850 (2014).
50. Meiby, E. et al. Fragment screening by weak affinity chromatography: comparison with established techniques for screening against HSP90. Anal. Chem. 85, 6756-6766 (2013).
51. Adams, J. M. et al. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 318, 533-538 (1985).