title: Design, Synthesis, and Cytotoxic Evaluation of Novel Tubulysin Analogues as ADC Payloads.
abstract: The 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.
authors.affiliation: Medicinal Sciences, Pfizer Worldwide R&D , Groton, Connecticut 06340, United States.
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Leverett
authors.affiliation: Medicinal Sciences, Pfizer Worldwide R&D , Groton, Connecticut 06340, United States.
authors.forename: Sai Chetan K
authors.initials: SC
authors.lastname: Sukuru
authors.affiliation: Medicinal Sciences, Pfizer Worldwide R&D , Groton, Connecticut 06340, United States.
authors.forename: Beth C
authors.initials: BC
authors.lastname: Vetelino
authors.affiliation: Oncology R&D, Pfizer Worldwide R&D , Pearl River, New York 10965, United States.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Musto
authors.affiliation: Medicinal Sciences, Pfizer Worldwide R&D , Groton, Connecticut 06340, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Parris
authors.affiliation: Medicinal Sciences, Pfizer Worldwide R&D , Groton, Connecticut 06340, United States.
authors.forename: Jayvardhan
authors.initials: J
authors.lastname: Pandit
authors.affiliation: Oncology R&D, Pfizer Worldwide R&D , Pearl River, New York 10965, United States.
authors.forename: Frank
authors.initials: F
authors.lastname: Loganzo
authors.affiliation: Medicinal Sciences, Pfizer Worldwide R&D , Groton, Connecticut 06340, United States.
authors.forename: Alison H
authors.initials: AH
authors.lastname: Varghese
authors.affiliation: Medicinal Sciences, Pfizer Worldwide R&D , Groton, Connecticut 06340, United States.
authors.forename: Guoyun
authors.initials: G
authors.lastname: Bai
authors.affiliation: Medicinal Sciences, Pfizer Worldwide R&D , Groton, Connecticut 06340, United States.
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.affiliation: Medicinal Sciences, Pfizer Worldwide R&D , Groton, Connecticut 06340, United States.
authors.forename: Dingguo
authors.initials: D
authors.lastname: Liu
authors.affiliation: Medicinal Sciences, Pfizer Worldwide R&D , Groton, Connecticut 06340, United States.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hudson
authors.affiliation: Medicinal Sciences, Pfizer Worldwide R&D , Groton, Connecticut 06340, United States.
authors.forename: Venkata Ramana
authors.initials: VR
authors.lastname: Doppalapudi
authors.affiliation: Medicinal Sciences, Pfizer Worldwide R&D , Groton, Connecticut 06340, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Stock
authors.affiliation: Medicinal Sciences, Pfizer Worldwide R&D , Groton, Connecticut 06340, United States.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.affiliation: Medicinal Sciences, Pfizer Worldwide R&D , Groton, Connecticut 06340, United States.
authors.forename: Chakrapani
authors.initials: C
authors.lastname: Subramanyam
keywords: Tubulysin; antibody−drug conjugates; microtubule inhibitors; parallel medicinal chemistry; rapid overlay of chemical structures; structure-based drug design; structure−activity relationships