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Structure-based development of new RAS-effector inhibitors from a combination of active and inactive RAS-binding compounds
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
Added On:
06/02/2019 09:45
Documents:
1811360116.full.pdf
Discipline Tags:
Non-Communicable Diseases
Health & Wellbeing
Cancer
Structural biology
Drug Discovery
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)