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TitleDiscovery of RMC-5552, a Selective Bi-Steric Inhibitor of mTORC1, for the Treatment of mTORC1-Activated Tumors.
Journal, issue, pagesJ Med Chem, Vol. 66, Issue 1, Page 149-169, Year 2023
Publish dateJan 12, 2023
AuthorsG 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 /
PubMed AbstractHyperactivation 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 ...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.
External linksJ Med Chem / PubMed:36533617 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.81 - 3.07 Å
Structure data

28551

8era

EMDB-28551, PDB-8era:
RMC-5552 in complex with mTORC1 and FKBP12
Method: EM (single particle) / Resolution: 2.86 Å

PDB-8er6:
FKBP12-FRB in Complex with Compound 11
Method: X-RAY DIFFRACTION / Resolution: 2.81 Å

PDB-8er7:
FKBP12-FRB in Complex with Compound 12
Method: X-RAY DIFFRACTION / Resolution: 3.07 Å

Chemicals

ChemComp-XYU:
(3S,5R,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,30R,34aS)-5,9,27-trihydroxy-3-{(2R)-1-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]propan-2-yl}-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-octadecahydro-3H-23,27-epoxypyrido[2,1-c][1,4]oxazacyclohentriacontine-1,11,28,29(4H,31H)-tetrone

ChemComp-EDO:
1,2-ETHANEDIOL / Ethylene glycol

ChemComp-HOH:
WATER / Water

ChemComp-XZ3:
(3S,5R,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,30R,34aS)-9,27-dihydroxy-3-{(2R)-1-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]propan-2-yl}-5,10,21-trimethoxy-6,8,12,14,20,26-hexamethyl-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-octadecahydro-3H-23,27-epoxypyrido[2,1-c][1,4]oxazacyclohentriacontine-1,11,28,29(4H,31H)-tetrone

ChemComp-CL:
Unknown entry / Chloride

ChemComp-XZ9:
1-[6-{[(3M)-4-amino-3-(2-amino-1,3-benzoxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl}-3,4-dihydroisoquinolin-2(1H)-yl]-3-hydroxypropan-1-one

Source
  • homo sapiens (human)
KeywordsCOMPLEX (ISOMERASE/KINASE) / Antitumor / mTORC1 / COMPLEX (ISOMERASE-KINASE) complex

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