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

DOI: 10.1073/pnas.1811360116 DOI Help

Authors: Abimael Cruz-migoni (John Radcliffe Hospital, University of Oxford; Complex at Harwell) , Peter Canning (John Radcliffe Hospital, University of Oxford) , Camilo E. Quevedo (John Radcliffe Hospital, University of Oxford) , Carole J. R. Bataille (University of Oxford) , Nicolas Bery (John Radcliffe Hospital, University of Oxford) , Ami Miller (John Radcliffe Hospital, University of Oxford) , Angela J. Russell (University of Oxford) , Simon E. V. Phillips (Research Complex at Harwell) , Stephen B. Carr (Research Complex at Harwell; University of Oxford) , Terence Rabbitts (John Radcliffe Hospital, University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Proceedings Of The National Academy Of Sciences , VOL 8

State: Published (Approved)
Published: January 2019
Diamond Proposal Number(s): 12346

Abstract: 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 KRAS169Q61H-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.

Journal Keywords: cancer; RAS; drugs; antibody; intracellular antibody

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography

Other Facilities: ESRF

Documents:
1811360116.full.pdf