ArticleEuropean journal of medicinal chemistry2018
Effects of rigidity on the selectivity of protein kinase inhibitors.
Article in European journal of medicinal chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
8 citing papers in PubMed, 14 citations in OpenAlex.
- Structure-Based Drug Discovery of Non-SAM-Mimetic Bisubstrate Inhibitors against NicotinamideACS medicinal chemistry letters · 2026Article
- Lead-Structure-Based Rigidization Approach to Optimize SirReal-Type Sirt2 Inhibitors.Molecules (Basel, Switzerland) · 2025Article
- Article
- Article
- Functional characterization of a PROTAC directed against BRAF mutant V600E.Nature chemical biology · 2020Article
- Biological Evaluation of Arylsemicarbazone Derivatives as Potential Anticancer Agents.Pharmaceuticals (Basel, Switzerland) · 2019Article
- Leveraging Atropisomerism to Obtain a Selective Inhibitor of RET Kinase with Secondary Activities toward EGFR Mutants.ACS chemical biology · 2019Article
- Rigidification Dramatically Improves Inhibitor Selectivity for RAF Kinases.ACS medicinal chemistry letters · 2019Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
Established strategies for discovering selective kinase inhibitors are target-centric as they often target certain structural or reactive features in the target kinase. In the absence of such prominent features, there is a lack of general methods for discovering selective inhibitors. Here we describe a new strategy that exploits conformational flexibility of kinases for achieving selective kinase inhibition. Through ring closure, we designed and synthesized a panel of isoquinoline-containing compounds as rigidified analogs of an amidophenyl-containing parent compound. These analogs potently inhibit kinases including Abl and BRAF but have diminished inhibition against some other kinases compared to the parent compound. Sequence analysis reveals that many of the kinases that are potently inhibited by the isoquonoline-containing compounds contain a long insertion within their catalytic domains. A crystal structure of one rigid compound bound to BRAF confirmed its binding mode. Our findings highlight the potential of a novel strategy of rigidification for improving the selectivity of kinase inhibitors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.