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

Cruz-Migoni A., Canning P., Quevedo CE., Bataille CJR., Bery N., Miller A., Russell AJ., Phillips SEV., Carr SB., Rabbitts TH.

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.

DOI

10.1073/pnas.1811360116

Type

Journal article

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Date

02/2019

Volume

116

Pages

2545 - 2550

Addresses

Weatherall Institute of Molecular Medicine, MRC Molecular Haematology Unit, John Radcliffe Hospital, University of Oxford, OX3 9DS Oxford, United Kingdom.

Keywords

Oncogene Protein p21(ras), Antineoplastic Agents, Crystallography, X-Ray, Surface Plasmon Resonance, Molecular Structure, Protein Binding, Drug Development

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