Design, Synthesis, and Structure-Activity Relationships of Novel Tetrahydroisoquinolino Benzodiazepine Dimer Antitumor Agents and Their Application in Antibody-Drug Conjugates

Naidu S Chowdari; Yong Zhang; Ivar McDonald; Walter Johnson; David R Langley; Prasanna Sivaprakasam; Robert Mate; Tram Huynh; Srikanth Kotapati; Madhura Deshpande; Chin Pan; Daniel Menezes; Yichong Wang; Chetana Rao; Ganapathy Sarma; Bethanne M Warrack; Vangipuram S Rangan; Sung Mei-Chen; Pina Cardarelli; Shrikant Deshpande; David Passmore; Richard Rampulla; Arvind Mathur; Robert Borzilleri; Arvind Rajpal; Gregory Vite; Sanjeev Gangwar

doi:10.1021/acs.jmedchem.0c01385

Design, Synthesis, and Structure-Activity Relationships of Novel Tetrahydroisoquinolino Benzodiazepine Dimer Antitumor Agents and Their Application in Antibody-Drug Conjugates

J Med Chem. 2020 Nov 25;63(22):13913-13950. doi: 10.1021/acs.jmedchem.0c01385. Epub 2020 Nov 6.

Authors

Naidu S Chowdari¹, Yong Zhang², Ivar McDonald³, Walter Johnson¹, David R Langley³, Prasanna Sivaprakasam³, Robert Mate¹, Tram Huynh², Srikanth Kotapati¹, Madhura Deshpande¹, Chin Pan¹, Daniel Menezes¹, Yichong Wang¹, Chetana Rao¹, Ganapathy Sarma¹, Bethanne M Warrack², Vangipuram S Rangan¹, Sung Mei-Chen¹, Pina Cardarelli¹, Shrikant Deshpande¹, David Passmore¹, Richard Rampulla², Arvind Mathur², Robert Borzilleri², Arvind Rajpal¹, Gregory Vite², Sanjeev Gangwar¹

Affiliations

¹ Bristol Myers Squibb Research & Early Development, 700 Bay Road, Redwood City, California 94063, United States.
² Bristol Myers Squibb Research & Early Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
³ Bristol Myers Squibb Research & Early Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States.

PMID: 33155811
DOI: 10.1021/acs.jmedchem.0c01385

Abstract

A series of tetrahydroisoquinoline-based benzodiazepine dimers were synthesized and tested for in vitro cytotoxicity against a panel of cancer cell lines. Structure-activity relationship investigation of various spacers guided by molecular modeling studies helped to identify compounds with picomolar activity. Payload 17 was conjugated to anti-mesothelin and anti-fucosylated monosialotetrahexosylganglioside (FucGM1) antibodies using lysosome-cleavable valine-citrulline dipeptide linkers via heterogeneous lysine conjugation and bacterial transglutaminase-mediated site-specific conjugation. In vitro, these antibody drug conjugates (ADCs) exhibited significant cytotoxic and target-mediated selectivity on human cancer cell lines. The pharmacokinetics and efficacy of these ADCs were further evaluated in gastric and lung cancer xenograft models in mice. Consistent pharmacokinetic profiles, high target specificity, and robust antitumor activity were observed in these models after a single dose of the ADC-46 (0.02 μmol/kg).

MeSH terms

Animals
Antibodies, Monoclonal / chemistry*
Antibodies, Monoclonal / immunology
Antibodies, Monoclonal / metabolism
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis
Benzodiazepines / chemistry*
Benzodiazepines / metabolism
Cell Proliferation
Drug Design*
Female
G(M1) Ganglioside / analogs & derivatives
G(M1) Ganglioside / immunology
GPI-Linked Proteins / immunology
Humans
Immunoconjugates / chemistry
Immunoconjugates / pharmacology*
Lung Neoplasms / drug therapy
Lung Neoplasms / pathology
Mesothelin
Mice
Mice, SCID
Small Cell Lung Carcinoma / drug therapy*
Small Cell Lung Carcinoma / pathology
Stomach Neoplasms / drug therapy*
Stomach Neoplasms / pathology
Structure-Activity Relationship
Tetrahydroisoquinolines / chemistry*
Tetrahydroisoquinolines / metabolism
Tumor Cells, Cultured
Xenograft Model Antitumor Assays

Substances

Antibodies, Monoclonal
Antineoplastic Agents
GPI-Linked Proteins
Immunoconjugates
Msln protein, mouse
Tetrahydroisoquinolines
Benzodiazepines
G(M1) Ganglioside
fucosyl GM1 ganglioside
Mesothelin