Structure-based development of new RAS-effector inhibitors from a combination of active and inactive RAS-binding compounds.
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Embargo End Date
ICR Authors
Authors
Cruz-Migoni, A
Canning, P
Quevedo, CE
Bataille, CJR
Bery, N
Miller, A
Russell, AJ
Phillips, SEV
Carr, SB
Rabbitts, TH
Canning, P
Quevedo, CE
Bataille, CJR
Bery, N
Miller, A
Russell, AJ
Phillips, SEV
Carr, SB
Rabbitts, TH
Document Type
Journal Article
Date
2019-02-12
Date Accepted
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.
Citation
Proceedings of the National Academy of Sciences of the United States of America, 2019, 116 (7), pp. 2545 - 2550
Source Title
Publisher
NATL ACAD SCIENCES
ISSN
0027-8424
eISSN
1091-6490
Collections
Research Team
Chromosomal Translocations and Intracellular Antibody Therapeutics