Structure-based development of new RAS-effector inhibitors from a combination of active and inactive RAS-binding compounds

The RAS gene family is frequently mutated in human cancers, and the quest for compounds that bind to mutant RAS remains a major goal, as it also does for inhibitors of protein–protein interactions. We have refined crystallization conditions for KRAS169 Q61H-yielding crystals suitable for soaking wit...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 116; no. 7; pp. 2545 - 2550
Main Authors Cruz-Migoni, Abimael, Canning, Peter, Quevedo, Camilo E., Bataille, Carole J. R., Bery, Nicolas, Miller, Ami, Russell, Angela J., Phillips, Simon E. V., Carr, Stephen B., Rabbitts, Terence H.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 12.02.2019
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Summary:The RAS gene family is frequently mutated in human cancers, and the quest for compounds that bind to mutant RAS remains a major goal, as it also does for inhibitors of protein–protein interactions. We have refined crystallization conditions for KRAS169 Q61H-yielding crystals suitable for soaking with compounds and exploited this to assess new RAS-binding compounds selected by screening a protein–protein interaction-focused compound library using surface plasmon resonance. Two compounds, referred to as PPIN-1 and PPIN-2, with related structures from 30 initial RAS binders showed binding to a pocket where compounds had been previously developed, including RAS effector protein–protein interaction inhibitors selected using an intracellular antibody fragment (called Abd compounds). Unlike the Abd series of RAS binders, PPIN-1 and PPIN-2 compounds were not competed by the inhibitory anti-RAS intracellular antibody fragment and did not show any RAS-effector inhibition properties. By fusing the common, anchoring part from the two new compounds with the inhibitory substituents of the Abd series, we have created a set of compounds that inhibit RAS-effector interactions with increased potency. These fused compounds add to the growing catalog of RAS protein–protein inhibitors and show that building a chemical series by crossing over two chemical series is a strategy to create RAS-binding small molecules.
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2Present address: Assay Development, LifeArc, Open Innovation Campus, SG1 2FX Stevenage, United Kingdom.
1A.C.-M., P.C., and C.E.Q. contributed equally to this work.
Edited by James A. Wells, University of California, San Francisco, CA, and approved December 17, 2018 (received for review July 6, 2018)
Author contributions: C.E.Q. and T.H.R. designed research; A.C.-M., P.C., C.J.R.B., N.B., and A.M. performed research; A.C.-M., P.C., C.E.Q., C.J.R.B., N.B., A.M., A.J.R., S.E.V.P., S.B.C., and T.H.R. analyzed data; and A.C.-M., P.C., C.E.Q., C.J.R.B., N.B., A.M., S.E.V.P., S.B.C., and T.H.R. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1811360116