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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 7; pp. 2545 - 2550
• Main Authors: Cruz-Migoni, Abimael, Canning, Peter, Quevedo, Camilo E., Bataille, Carole J. R., Bery, Nicolas, Miller, Ami, Russell, Angela J., Phillips, Simon E. V., Carr, Stephen B., Rabbitts, Terence H.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 12.02.2019
• Subjects: Anchoring; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Binders; Binding; Biological Sciences; Crystallization; Crystallography, X-Ray; Crystals; Drug Development; Inhibitors; Intracellular; 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; cancer; antibody; RAS; drugs; intracellular antibody
• DOI: 10.1073/pnas.1811360116
• ISSN: 0027-8424

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.