Saturday, November 9, 2019

Structure–Activity Relationship Study of Covalent Pan-phosphatidylinositol 5-Phosphate 4-Kinase Inhibitors

Theresa D. ManzSindhu C. SivakumarenAdam YasgarMatthew D. HallMindy I. DavisHyuk-Soo SeoJoseph D. CardScott B. FicarroHyeseok ShimJarrod A. MartoSirano Dhe-PaganonAtsuo T. SasakiMatthew B. BoxerAnton SimeonovLewis C. CantleyMin ShenTinghu ZhangFleur M. Ferguson, and Nathanael S. Gray

ACS Medicinal Chemistry Letters  2019DOI: 10.1021/acsmedchemlett.9b00402

Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are important molecular players in a variety of diseases, such as cancer. Currently available PI5P4K inhibitors are reversible small molecules, which may lack selectivity and sufficient cellular on-target activity. In this study, we present a new class of covalent pan-PI5P4K inhibitors with potent biochemical and cellular activity. Our designs are based on THZ-P1-2, a covalent PI5P4K inhibitor previously developed in our lab. Here, we report further structure-guided optimization and structure–activity relationship (SAR) study of this scaffold, resulting in compound 30, which retained biochemical and cellular potency, while demonstrating a significantly improved selectivity profile. Furthermore, we confirm that the inhibitors show efficient binding affinity in the context of HEK 293T cells using isothermal CETSA methods. Taken together, compound 30 represents a highly selective pan-PI5P4K covalent lead molecule.

Oncogenic KRAS G12C: Kinetic and Redox Characterization of Covalent Inhibition

Minh V. Huynh, Derek Parsonage, Tom E. Forshaw, Venkat R. Chirasani, G. Aaron Hobbs, Hanzhi Wu, Jingyun Lee, Cristina M. Furdui, Leslie B. P...