posted on 2024-01-09, 13:03authored byLiqi 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
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.