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

• Published in: ACS medicinal chemistry letters Vol. 15; no. 2; pp. 189 - 196
• Main Authors: He, Liqi, Zhang, Meng Yao, Cox, Matthew, Zhang, Qian, Donnell, Andrew F., Zhang, Yong, Tarby, Christine, Gill, Patrice, Subbaiah, Murugaiah A. M., Ramar, Thangeswaran, Reddy, Maheswara, Puttapaka, Vijaya, Li, Yi-Xin, Sivaprakasam, Prasanna, Critton, David, Mulligan, Dawn, Xie, Chunshan, Ramakrishnan, Radha, Nagar, Jignesh, Dudhgaonkar, Shailesh, Murtaza, Anwar, Oderinde, Martins S., Schieven, Gary L., Mathur, Arvind, Gavai, Ashvinikumar V., Vite, Gregory, Gangwar, Sanjeev, Poudel, Yam B.
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 08.02.2024; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; Tumor; TLR7 agonist; PD1; Immuno-oncology; Cancer
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.3c00456

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.