Ayah Abdeldayem, Yasir S. Raouf, Stefan N. Constantinescu, Richard Moriggl, and Patrick T. Gunning
Chem. Soc. Rev., 2020
https://doi.org/10.1039/C9CS00720B
Over the past decade, covalent kinase inhibitors (CKI) have seen a resurgence in drug discovery. Covalency affords a unique set of advantages as well as challenges relative to their non-covalent counterpart. After reversible protein target recognition and binding, covalent inhibitors irreversibly modify a proximal nucleophilic residue on the protein via reaction with an electrophile. To date, the acrylamide group remains the predominantly employed electrophile in CKI development, with its incorporation in the majority of clinical candidates and FDA approved covalent therapies. Nonetheless, in recent years considerable efforts have ensued to characterize alternative electrophiles that exhibit irreversible or reversibly covalent binding mechanisms towards cysteine thiols and other amino acids. This review article provides a comprehensive overview of CKIs reported in the literature over a decade period, 2007–2018. Emphasis is placed on the rationale behind warhead choice, optimization approach, and inhibitor design. Current FDA approved CKIs are also highlighted, in addition to a detailed analysis of the common trends and themes observed within the listed data set.
A blog highlighting recent publications in the area of covalent modification of proteins, particularly relating to covalent-modifier drugs. @CovalentMod on Twitter, @covalentmod@mstdn.science on Mastodon, and @covalentmod.bsky.social on BlueSky
Rapid, potent, and persistent covalent chemical probes to deconvolute PI3Kα signaling
Lukas Bissegger, Theodora A. Constantin, Erhan Keles, Luka Raguž, Isobel Barlow-Busch, Clara Orbegozo, Thorsten Schaefer, Valentina...
-
Linqi Cheng Yixian Wang, Yiming Guo, Sophie S. Zhang Han Xiao C ell Chemical Biology, 2024 Volume 31, 3, 428 - 445 https://doi.org/10.10...
-
Nathalie M. Grob, Clint Remarcik, Simon L. Rössler, Jeffrey Y. K. Wong, John C. K. Wang, Jason Tao, Corey L. Smith, Andrei Loas, Stephen L. ...
-
Guanghui Tang , Wei Wang , Chengjun Zhu , Huisi Huang , Peng Chen , Xuan Wang , Manyi Xu , Jie Sun , Chong-Jing Zhang , Qicai Xiao ...