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

被引：2

作者：

He, Liqi ^{[1
]}

Zhang, Meng Yao ^{[1
]}

Cox, Matthew ^{[1
]}

Zhang, Qian ^{[1
]}

Donnell, Andrew F. ^{[2
]}

Zhang, Yong ^{[2
]}

Tarby, Christine ^{[2
]}

Gill, Patrice ^{[2
]}

Subbaiah, Murugaiah A. M. ^{[3
]}

Ramar, Thangeswaran ^{[3
]}

Reddy, Maheswara ^{[3
]}

Puttapaka, Vijaya ^{[3
]}

Li, Yi-Xin ^{[1
]}

Sivaprakasam, Prasanna ^{[2
]}

Critton, David ^{[2
]}

Mulligan, Dawn ^{[2
]}

Xie, Chunshan ^{[2
]}

Ramakrishnan, Radha ^{[2
]}

Nagar, Jignesh ^{[3
]}

Dudhgaonkar, Shailesh ^{[3
]}

Murtaza, Anwar ^{[2
]}

Oderinde, Martins S. ^{[2
]}

Schieven, Gary L. ^{[2
]}

Mathur, Arvind ^{[2
]}

Gavai, Ashvinikumar V. ^{[2
]}

Vite, Gregory ^{[2
]}

Gangwar, Sanjeev ^{[1
]}

Poudel, Yam B. ^{[1
]}

机构：

[1] Bristol Myers Squibb, Res & Dev, Redwood City, CA 94063 USA

[2] Bristol Myers Squibb, Res & Dev, Princeton, NJ 08543 USA

[3] Biocon Bristol Myers Squibb R&D Ctr, Bangalore 560099, India

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2024年 / 15卷 / 02期

关键词：

TLR7; agonist; Tumor; Immuno-oncology; Cancer; PD1;

D O I：

10.1021/acsmedchemlett.3c00456

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：189 / 196

页数：8

共 48 条

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