5kx5
Crystal structure of tubulin-stathmin-TTL-Compound 11 complex
Structural highlights
FunctionD0VWZ0_SHEEP 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 (By similarity).[RuleBase:RU003505][SAAS:SAAS023123_004_019801] Publication Abstract from PubMedThe tubulysin class of natural products has attracted much attention from the medicinal chemistry community due to its potent cytotoxicity against a wide range of human cancer cell lines, including significant activity in multidrug-resistant carcinoma models. As a result of their potency, the tubulysins have become an important tool for use in targeted therapy, being widely pursued as payloads in the development of novel small molecule drug conjugates (SMDCs) and antibody-drug conjugates (ADCs). A structure-based and parallel medicinal chemistry approach was applied to the synthesis of novel tubulysin analogues. These efforts led to the discovery of a number of novel and potent cytotoxic tubulysin analogues, providing a framework for our simultaneous report, which highlights the discovery of tubulysin-based ADCs, including use of site-specific conjugation to address in vivo stability of the C-11 acetate functionality. Design, Synthesis, and Cytotoxic Evaluation of Novel Tubulysin Analogues as ADC Payloads.,Leverett CA, Sukuru SC, Vetelino BC, Musto S, Parris K, Pandit J, Loganzo F, Varghese AH, Bai G, Liu B, Liu D, Hudson S, Doppalapudi VR, Stock J, O'Donnell CJ, Subramanyam C ACS Med Chem Lett. 2016 Aug 26;7(11):999-1004. eCollection 2016 Nov 10. PMID:27882198[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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