8ER7

FKBP12-FRB in Complex with Compound 12

Summary for 8ER7

• Entry DOI: 10.2210/pdb8er7/pdb
• Descriptor: Peptidyl-prolyl cis-trans isomerase FKBP1A, non-specific serine/threonine protein kinase, (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, ... (5 entities in total)
• Functional Keywords: antitumor, mtorc1, complex (isomerase-kinase) complex, complex (isomerase/kinase)
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 72799.27

Authors

Tomlinson, A.C.A.,Yano, J.K. (deposition date: 2022-10-11, release date: 2022-12-28, Last modification date: 2023-10-25)

Primary citation

Burnett, G.L.,Yang, Y.C.,Aggen, J.B.,Pitzen, J.,Gliedt, M.K.,Semko, C.M.,Marquez, A.,Evans, J.W.,Wang, G.,Won, W.S.,Tomlinson, A.C.A.,Kiss, G.,Tzitzilonis, C.,Thottumkara, A.P.,Cregg, J.,Mellem, K.T.,Choi, J.S.,Lee, J.C.,Zhao, Y.,Lee, B.J.,Meyerowitz, J.G.,Knox, J.E.,Jiang, J.,Wang, Z.,Wildes, D.,Wang, Z.,Singh, M.,Smith, J.A.M.,Gill, A.L.
Discovery of RMC-5552, a Selective Bi-Steric Inhibitor of mTORC1, for the Treatment of mTORC1-Activated Tumors.
J.Med.Chem., 66:149-169, 2023

PubMed 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.

PubMed: 36533617
DOI: 10.1021/acs.jmedchem.2c01658

Experimental method

X-RAY DIFFRACTION (3.07 Å)