期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 7, 页码 2545-2550出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1811360116
关键词
cancer; RAS; drugs; antibody; intracellular antibody
资金
- Engineering and Physical Sciences Research Council [EP/I037210/1, EP/I037172/1]
- Wellcome Trust [099246/Z/12/Z, 100842/Z/12/Z]
- Medical Research Council [MR/J000612/1]
- Bloodwise [12051]
- EPSRC [EP/I037210/1] Funding Source: UKRI
- MRC [MR/J000612/1] Funding Source: UKRI
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 KRAS(169)(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.
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