Journal Article

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

Miller, Ami, Phillips, Simon E. V., Carr, Stephen B., Bataille, Carole J. R., Bery, Nicolas, Canning, Peter, Russell, Angela J., Cruz-Migoni, Abimael, Quevedo, Camilo E., Rabbitts, Terence H.

2019

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Anchoring / Antineoplastic Agents - chemistry / Antineoplastic Agents - pharmacology / Binders / Binding / Biochemistry / Biochemistry, Molecular Biology / Biological Sciences / Cancer / Crystallization / Crystallography, X-Ray / Crystals / Drug Development / Inhibitors / Intracellular / Life Sciences / Molecular Structure / Oncogene Protein p21(ras) - antagonists & inhibitors / Oncogene Protein p21(ras) - metabolism / Organic chemistry / Protein Binding / Protein interaction / Proteins / Ras protein / Surface Plasmon Resonance