monomethyl-auristatin-e and dolastatin-10

In order to further explore quinoline-type structural modification of the powerful anticancer drug dolastatin 10, an Indian Ocean sea hare constituent and parent molecule of the very successful antibody drug conjugate (ADC) Adcetris, our recent quinstatin study has been extended by replacing the quinoline ring with an isoquinoline. The resulting isoquinstatins (4-6) were modified to N-terminal desmethylisoquinstatins (7-9) and, in turn, bonded to appropriate linker units to give linker-desmethylisoquinstatin conjugates 11-13 in preparation for eventual monoclonal antibody attachment. Comparison of the new isoquinstatins with their quinstatin counterparts against six human cancer cell lines indicated the isoquinstatins to have GI

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Depsipeptides; Humans; Indian Ocean; Quinolines

Dolastatin 10 (1) is a highly potent cytotoxic microtubule inhibitor (cytotoxicity IC

Topics: Alcohols; Amines; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Depsipeptides; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Mice; Molecular Structure; Structure-Activity Relationship; Sulfhydryl Compounds; Thiazoles; Tubulin

Discovery of the exceptionally powerful anticancer drug dolastatin 10 (1), contained in the sea hare Dolabella auricularia, opened a new frontier needed for improving human cancer treatment. Subsequently, major advances have been achieved based on results of structurally modifying this unusual natural peptide while maintaining the remarkable anticancer activity necessary for preparation of successful monoclonal antibody drug conjugates (ADC). Among the first several hundred SAR products based on dolastatin 10 our group synthesized and termed auristatins was auristatin E (2a). An anticancer activity-equivalent, desmethylaurisatin E (2b), linked to a CD30 monoclonal antibody is the very successful anticancer drug Adcetris, now approved for use in 65 countries. In the present investigation, we discovered a new subset of auristatins designated quinstatins derived from dolastatin 10 by replacing the C-terminal Doe unit with a carefully designed quinoline, which led to low or subnanomolar levels of cancer cell growth inhibition required for construction of chemically unique ADC drugs. The synthesis of quinstatins 2-8 is presented along with their cancer cell line biological data.

Topics: Aminobenzoates; Animals; Antibodies, Monoclonal; Antineoplastic Agents; Brentuximab Vedotin; Depsipeptides; Drug Screening Assays, Antitumor; Gastropoda; Humans; Immunoconjugates; Molecular Structure; Oligopeptides

To further evaluate the exceptional cancer cell growth inhibition by the quinstatins, of which one of the series, quinstatin 8, approaches the exceptional cytotoxic activity of the parent dolastatin 10 (1), four of the quinstatins have been converted to desmethyl derivatives. Three of the four (4, 5, and 8 [7b-d]) were next bonded to the linker (8) employed in the synthesis of the very successful and structurally related anticancer drug Adcetris (3). Owing to these structural modifications, a next step could be taken by bonding to a monoclonal antibody, thereby producing an antibody drug conjugate (ADC) related to Adcetris structurally but with the possibility of a wider spectrum of activity and utility.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Brentuximab Vedotin; Depsipeptides; Humans; Immunoconjugates; Molecular Structure

Auristatins, synthetic analogues of the antineoplastic natural product Dolastatin 10, are ultrapotent cytotoxic microtubule inhibitors that are clinically used as payloads in antibody-drug conjugates (ADCs). The design and synthesis of several new auristatin analogues with N-terminal modifications that include amino acids with α,α-disubstituted carbon atoms are described, including the discovery of our lead auristatin, PF-06380101. This modification of the peptide structure is unprecedented and led to analogues with excellent potencies in tumor cell proliferation assays and differential ADME properties when compared to other synthetic auristatin analogues that are used in the preparation of ADCs. In addition, auristatin cocrystal structures with tubulin are being presented that allow for the detailed examination of their binding modes. A surprising finding is that all analyzed analogues have a cis-configuration at the Val-Dil amide bond in their functionally relevant tubulin bound state, whereas in solution this bond is exclusively in the trans-configuration. This remarkable observation shines light onto the preferred binding mode of auristatins and serves as a valuable tool for structure-based drug design.

Topics: Animals; Antineoplastic Agents; Area Under Curve; Cell Proliferation; Cells, Cultured; Crystallography, X-Ray; Depsipeptides; Drug Discovery; Drug Screening Assays, Antitumor; Hepatocytes; Humans; Male; Microsomes, Liver; Models, Molecular; Molecular Structure; Neoplasms; Protein Conformation; Rats; Rats, Wistar; Structure-Activity Relationship; Tandem Mass Spectrometry; Tubulin