Discovery of RMC-5552, a Selective Bi-Steric Inhibitor of MTORC1, for the Treatment of MTORC1-Activated Tumors

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2022 Dec 19

PMID 36533617

Authors

G Leslie Burnett

Yu C Yang

James B Aggen

Jennifer Pitzen

Micah K Gliedt

Chris M Semko

Abby Marquez

James W Evans

Gang Wang

Walter S Won

Aidan C A Tomlinson

Gert Kiss

Christos Tzitzilonis

Arun P Thottumkara

James Cregg

Kevin T Mellem

Jong S Choi

Julie C Lee

Yongyuan Zhao

Bianca J Lee

Justin G Meyerowitz

John E Knox

Jingjing Jiang

Zhican Wang

David Wildes

Zhengping Wang

Mallika Singh

Jacqueline A M Smith

Adrian L Gill

Affiliations

Soon will be listed here.

Abstract

Hyperactivation of mTOR kinase by mutations in the PI3K/mTOR pathway or by crosstalk with other mutant cancer drivers, such as RAS, is a feature of many tumors. Multiple allosteric inhibitors of mTORC1 and orthosteric dual inhibitors of mTORC1 and mTORC2 have been developed as anticancer drugs, but their clinical utility has been limited. To address these limitations, we have developed a novel class of "bi-steric inhibitors" that interact with both the orthosteric and the allosteric binding sites in order to deepen the inhibition of mTORC1 while also preserving selectivity for mTORC1 over mTORC2. In this report, we describe the discovery and preclinical profile of the development candidate RMC-5552 and the in vivo preclinical tool compound RMC-6272. We also present evidence that selective inhibition of mTORC1 in combination with covalent inhibition of KRAS shows increased antitumor activity in a preclinical model of mutant NSCLC that exhibits resistance to KRAS inhibitor monotherapy.

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References

Scaiola A, Mangia F, Imseng S, Boehringer D, Berneiser K, Shimobayashi M . The 3.2-Å resolution structure of human mTORC2. Sci Adv. 2020; 6(45). PMC: 7673708. DOI: 10.1126/sciadv.abc1251. View

Paine M, Leung L, Watkins P . New insights into drug absorption: studies with sirolimus. Ther Drug Monit. 2004; 26(5):463-7. DOI: 10.1097/00007691-200410000-00001. View

Isotani S, Hara K, Tokunaga C, Inoue H, Avruch J, Yonezawa K . Immunopurified mammalian target of rapamycin phosphorylates and activates p70 S6 kinase alpha in vitro. J Biol Chem. 1999; 274(48):34493-8. DOI: 10.1074/jbc.274.48.34493. View

Musa J, Orth M, Dallmayer M, Baldauf M, Pardo C, Rotblat B . Eukaryotic initiation factor 4E-binding protein 1 (4E-BP1): a master regulator of mRNA translation involved in tumorigenesis. Oncogene. 2016; 35(36):4675-88. DOI: 10.1038/onc.2015.515. View

Baker H, SIDOROWICZ A, Sehgal S, Vezina C . Rapamycin (AY-22,989), a new antifungal antibiotic. III. In vitro and in vivo evaluation. J Antibiot (Tokyo). 1978; 31(6):539-45. DOI: 10.7164/antibiotics.31.539. View

Choo A, Yoon S, Kim S, Roux P, Blenis J . Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation. Proc Natl Acad Sci U S A. 2008; 105(45):17414-9. PMC: 2582304. DOI: 10.1073/pnas.0809136105. View

Kino T, Hatanaka H, Hashimoto M, Nishiyama M, Goto T, OKUHARA M . FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot (Tokyo). 1987; 40(9):1249-55. DOI: 10.7164/antibiotics.40.1249. View

Rodrik-Outmezguine V, Okaniwa M, Yao Z, Novotny C, McWhirter C, Banaji A . Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor. Nature. 2016; 534(7606):272-6. PMC: 4902179. DOI: 10.1038/nature17963. View

Zhang S, Nagasaka M . Spotlight on Sotorasib (AMG 510) for Positive Non-Small Cell Lung Cancer. Lung Cancer (Auckl). 2021; 12:115-122. PMC: 8504654. DOI: 10.2147/LCTT.S334623. View

10.

Yang H, Rudge D, Koos J, Vaidialingam B, Yang H, Pavletich N . mTOR kinase structure, mechanism and regulation. Nature. 2013; 497(7448):217-23. PMC: 4512754. DOI: 10.1038/nature12122. View

11.

Morris R . Rapamycin: FK506's fraternal twin or distant cousin?. Immunol Today. 1991; 12(5):137-40. DOI: 10.1016/S0167-5699(05)80040-4. View

12.

Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung S . SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell. 2006; 127(1):125-37. DOI: 10.1016/j.cell.2006.08.033. View

13.

Skoulidis F, Goldberg M, Greenawalt D, Hellmann M, Awad M, Gainor J . Mutations and PD-1 Inhibitor Resistance in -Mutant Lung Adenocarcinoma. Cancer Discov. 2018; 8(7):822-835. PMC: 6030433. DOI: 10.1158/2159-8290.CD-18-0099. View

14.

Paine M, Leung L, Lim H, Liao K, Oganesian A, Zhang M . Identification of a novel route of extraction of sirolimus in human small intestine: roles of metabolism and secretion. J Pharmacol Exp Ther. 2002; 301(1):174-86. DOI: 10.1124/jpet.301.1.174. View

15.

Kunz J, Henriquez R, Schneider U, Movva N, Hall M . Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression. Cell. 1993; 73(3):585-96. DOI: 10.1016/0092-8674(93)90144-f. View

16.

Calne R, Collier D, Lim S, Pollard S, Samaan A, White D . Rapamycin for immunosuppression in organ allografting. Lancet. 1989; 2(8656):227. DOI: 10.1016/s0140-6736(89)90417-0. View

17.

Brown W, McDonald P, Nemirovsky O, Awrey S, Chafe S, Schaeffer D . Overcoming Adaptive Resistance to KRAS and MEK Inhibitors by Co-targeting mTORC1/2 Complexes in Pancreatic Cancer. Cell Rep Med. 2020; 1(8):100131. PMC: 7691443. DOI: 10.1016/j.xcrm.2020.100131. View

18.

Martel R, Klicius J, Galet S . Inhibition of the immune response by rapamycin, a new antifungal antibiotic. Can J Physiol Pharmacol. 1977; 55(1):48-51. DOI: 10.1139/y77-007. View

19.

Sehgal S, Baker H, Vezina C . Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J Antibiot (Tokyo). 1975; 28(10):727-32. DOI: 10.7164/antibiotics.28.727. View

20.

Bowes J, Brown A, Hamon J, Jarolimek W, Sridhar A, Waldron G . Reducing safety-related drug attrition: the use of in vitro pharmacological profiling. Nat Rev Drug Discov. 2012; 11(12):909-22. DOI: 10.1038/nrd3845. View