Structural analysis and binding sites of inhibitors targeting the CD47/SIRPα interaction in anticancer therapy

Bo Huang; Zhaoshi Bai; Xinyue Ye; Chenyu Zhou; Xiaolin Xie; Yuejiao Zhong; Kejiang Lin; Lingman Ma

doi:10.1016/j.csbj.2021.09.036

Structural analysis and binding sites of inhibitors targeting the CD47/SIRPα interaction in anticancer therapy

Comput Struct Biotechnol J. 2021 Oct 1:19:5494-5503. doi: 10.1016/j.csbj.2021.09.036. eCollection 2021.

Authors

Bo Huang¹, Zhaoshi Bai², Xinyue Ye³, Chenyu Zhou³, Xiaolin Xie^{1

3}, Yuejiao Zhong², Kejiang Lin¹, Lingman Ma^{1

3}

Affiliations

¹ Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 639 Longmian Road, Nanjing, Jiangsu 211198, China.
² Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & the Affiliated Cancer Hospital of Nanjing Medical University, Baiziting 42, Nanjing, Jiangsu 210009, China.
³ School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Road, Nanjing, Jiangsu 211198, China.

Abstract

Cluster of differentiation 47 (CD47)/signal regulatory protein alpha (SIRPα) is a negative innate immune checkpoint signaling pathway that restrains immunosurveillance and immune clearance, and thus has aroused wide interest in cancer immunotherapy. Blockade of the CD47/SIRPα signaling pathway shows remarkable antitumor effects in clinical trials. Currently, all inhibitors targeting CD47/SIRPα in clinical trials are biomacromolecules. The poor permeability and undesirable oral bioavailability of biomacromolecules have caused researchers to develop small-molecule CD47/SIRPα pathway inhibitors. This review will summarize the recent advances in CD47/SIRPα interactions, including crystal structures, peptides and small molecule inhibitors. In particular, we have employed computer-aided drug discovery (CADD) approaches to analyze all the published crystal structures and docking results of small molecule inhibitors of CD47/SIRPα, providing insight into the key interaction information to facilitate future development of small molecule CD47/SIRPα inhibitors.

Keywords: CD47/SIRPα; Computer-aided drug discovery; Crystal structure; Hot spot; Immunotherapy; Inhibitor.

Publication types

Review