7jfr
Auristatin bound to tubulin
Structural highlights
FunctionTBA1B_BOVIN Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain. Publication Abstract from PubMedAuristatins, a class of clinically validated anti-tubulin agents utilized as payloads in antibody-drug conjugates, are generally classified by their membrane permeability and the extent of cytotoxic bystander activity on neighboring cells after targeted delivery. The drugs typically fall within two categories: membrane permeable monomethyl auristatin E-type molecules with high bystander activities and susceptibility to efflux pumps, or charged and less permeable monomethyl auristatin F (MMAF) analogs with low bystander activities and resistance to efflux pumps. Herein, we report the development of novel auristatins that combine the attributes of each class by having both bystander activity and cytotoxicity on multidrug-resistant (MDR(+)) cell lines. Structure-based design focused on the hydrophobic functionalization of the N-terminal N-methylvaline of the MMAF scaffold to increase cell permeability. The resulting structure-activity relationships of the new auristatins demonstrate that optimization of hydrophobicity and structure can lead to highly active free drugs and antibody-drug conjugates with in vivo bystander activities. Novel Auristatins with High Bystander and Cytotoxic Activities in Drug Efflux-positive Tumor Models.,Moquist PN, Bovee TD, Waight AB, Mitchell JA, Miyamoto JB, Mason ML, Emmerton KK, Stevens N, Balasubramanian C, Simmons JK, Lyon RP, Senter PD, Doronina SO Mol Cancer Ther. 2021 Feb;20(2):320-328. doi: 10.1158/1535-7163.MCT-20-0618. Epub , 2020 Dec 7. PMID:33288628[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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