Identification and Optimization of Small Molecule Pyrazolopyrimidine TLR7 Agonists for Applications in Immuno-oncology

Liqi He; Meng Yao Zhang; Matthew Cox; Qian Zhang; Andrew F Donnell; Yong Zhang; Christine Tarby; Patrice Gill; Murugaiah A M Subbaiah; Thangeswaran Ramar; Maheswara Reddy; Vijaya Puttapaka; Yi-Xin Li; Prasanna Sivaprakasam; David Critton; Dawn Mulligan; Chunshan Xie; Radha Ramakrishnan; Jignesh Nagar; Shailesh Dudhgaonkar; Anwar Murtaza; Martins S Oderinde; Gary L Schieven; Arvind Mathur; Ashvinikumar V Gavai; Gregory Vite; Sanjeev Gangwar; Yam B Poudel

doi:10.1021/acsmedchemlett.3c00456

Identification and Optimization of Small Molecule Pyrazolopyrimidine TLR7 Agonists for Applications in Immuno-oncology

ACS Med Chem Lett. 2024 Jan 9;15(2):189-196. doi: 10.1021/acsmedchemlett.3c00456. eCollection 2024 Feb 8.

Authors

Liqi He¹, Meng Yao Zhang¹, Matthew Cox¹, Qian Zhang¹, Andrew F Donnell², Yong Zhang², Christine Tarby², Patrice Gill², Murugaiah A M Subbaiah³, Thangeswaran Ramar³, Maheswara Reddy³, Vijaya Puttapaka³, Yi-Xin Li¹, Prasanna Sivaprakasam², David Critton², Dawn Mulligan², Chunshan Xie², Radha Ramakrishnan², Jignesh Nagar³, Shailesh Dudhgaonkar³, Anwar Murtaza², Martins S Oderinde², Gary L Schieven², Arvind Mathur², Ashvinikumar V Gavai², Gregory Vite², Sanjeev Gangwar¹, Yam B Poudel¹

Affiliations

¹ Research and Development, Bristol Myers Squibb, 700 Bay Road, Redwood City, California 94063, United States.
² Research and Development, Bristol Myers Squibb, Princeton, New Jersey 08543, United States.
³ Biocon Bristol Myers Squibb R&D Centre, Bangalore 560099, India.

PMID: 38352849
PMCID: PMC10860188 (available on 2025-02-08)
DOI: 10.1021/acsmedchemlett.3c00456

Abstract

Small molecule toll-like receptor (TLR) 7 agonists have gathered considerable interest as promising therapeutic agents for applications in cancer immunotherapy. Herein, we describe the development and optimization of a series of novel TLR7 agonists through systematic structure-activity relationship studies focusing on modification of the phenylpiperidine side chain. Additional refinement of ADME properties culminated in the discovery of compound 14, which displayed nanomolar reporter assay activity and favorable drug-like properties. Compound 14 demonstrated excellent in vivo pharmacokinetic/pharmacodynamic profiles and synergistic antitumor activity when administered in combination with aPD1 antibody, suggesting opportunities of employing 14 in immuno-oncology therapies with immune checkpoint blockade agents.