7JFR

Auristatin bound to tubulin

Summary for 7JFR

• Entry DOI: 10.2210/pdb7jfr/pdb
• Related PRD ID: PRD_002435
• Descriptor: Tubulin alpha-1B chain, PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER, Tubulin beta-2B chain, ... (11 entities in total)
• Functional Keywords: auristatin, tubulin, antimitotic, cell cycle
• Biological source: Rattus norvegicus (Rat); More
• Total number of polymer chains: 7
• Total formula weight: 261237.38

Authors

Moquist, P.N.,Waight, A. (deposition date: 2020-07-17, release date: 2020-09-16, Last modification date: 2023-11-15)

Primary citation

Moquist, P.N.,Bovee, T.D.,Waight, A.B.,Mitchell, J.A.,Miyamoto, J.B.,Mason, M.L.,Emmerton, K.K.,Stevens, N.,Balasubramanian, C.,Simmons, J.K.,Lyon, R.P.,Senter, P.D.,Doronina, S.O.
Novel Auristatins with High Bystander and Cytotoxic Activities in Drug Efflux-positive Tumor Models.
Mol.Cancer Ther., 20:320-328, 2021

PubMed Abstract: Auristatins, 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 -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 bystander activities.

PubMed: 33288628
DOI: 10.1158/1535-7163.MCT-20-0618

Experimental method

X-RAY DIFFRACTION (2.35 Å)