2. Academic Validation
  3. Structural Basis for Highly Selective Class II Alpha Phosphoinositide-3-Kinase Inhibition

Structural Basis for Highly Selective Class II Alpha Phosphoinositide-3-Kinase Inhibition

  • J Med Chem. 2023 Oct 26;66(20):14278-14302. doi: 10.1021/acs.jmedchem.3c01319.
Murat Kücükdisli 1,  Hassen Bel-Abed 1,  Davide Cirillo 1,  Wen-Ting Lo 1,  Nina-Louisa Efrém 1,  André Horatscheck 1,  Liudmila Perepelittchenko 1,  Polina Prokofeva 2,  Theresa A L Ehret 3 4,  Silke Radetzki 1,  Martin Neuenschwander 1,  Edgar Specker 1,  Guillaume Médard 2,  Susanne Müller 3 4,  Stephanie Wilhelm 2,  Bernhard Kuster 2,  Jens Peter von Kries 1,  Volker Haucke 1,  Marc Nazaré 1
Affiliations

Affiliations

  • 1 Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Campus Berlin-Buch, 13125 Berlin, Germany.
  • 2 Chair of Proteomics and Bioanalytics, Technical University of Munich, 85354 Freising, Germany.
  • 3 Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.
  • 4 Buchmann Institute for Molecular Life Sciences and Structural Genomics Consortium (SGC), Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany.
PMID: 37819647 DOI: 10.1021/acs.jmedchem.3c01319
Abstract

Class II phosphoinositide-3-kinases (PI3Ks) play central roles in cell signaling, division, migration, and survival. Despite evidence that all PI3K class II isoforms serve unique cellular functions, the lack of isoform-selective inhibitors severely hampers the systematic investigation of their potential relevance as pharmacological targets. Here, we report the structural evaluation and molecular determinants for selective PI3K-C2α inhibition by a structure-activity relationship study based on a pteridinone scaffold, leading to the discovery of selective PI3K-C2α inhibitors called PITCOINs. Cocrystal structures and docking experiments supported the rationalization of the structural determinants essential for inhibitor activity and high selectivity. Profiling of PITCOINs in a panel of more than 118 diverse kinases showed no off-target kinase inhibition. Notably, by addressing a selectivity pocket, PITCOIN4 showed nanomolar inhibition of PI3K-C2α and >100-fold selectivity in a general kinase panel. Our study paves the way for the development of novel therapies for diseases related to PI3K-C2α function.

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