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
Research and Development, Bristol Myers Squibb, 700 Bay Road, Redwood City, California 94063, United States.
Research and Development, Bristol Myers Squibb, Princeton, New Jersey 08543, United States.
ACS Med Chem Lett. 2024 Jan 9;15(2):189-196. doi: 10.1021/acsmedchemlett.3c00456. eCollection 2024 Feb 8.
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 , which displayed nanomolar reporter assay activity and favorable drug-like properties. Compound demonstrated excellent pharmacokinetic/pharmacodynamic profiles and synergistic antitumor activity when administered in combination with aPD1 antibody, suggesting opportunities of employing in immuno-oncology therapies with immune checkpoint blockade agents.
小分子Toll样受体（TLR）7激动剂作为癌症免疫治疗中有前景的治疗药物已引起了广泛关注。在此，我们通过聚焦于苯哌啶侧链修饰的系统构效关系研究，描述了一系列新型TLR7激动剂的开发与优化。对药物吸收、分布、代谢和排泄（ADME）性质的进一步优化最终发现了化合物，其在纳米摩尔报告基因检测中表现出活性，并具有良好的类药性质。化合物在与αPD1抗体联合给药时表现出优异的药代动力学/药效学特征和协同抗肿瘤活性，这表明其有机会与免疫检查点阻断剂联合用于免疫肿瘤治疗。
