Journal Article

PUBDB-2023-07433

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Design, Synthesis, and Antitumor Activity Evaluation of 2-Arylmethoxy-4-(2,2′-dihalogen-substituted biphenyl-3-ylmethoxy) Benzylamine Derivatives as Potent PD-1/PD-L1 Inhibitors

Zhang, H. ; Zhou, S. ; Plewka, J.Extern* ; Wu, C. ; Zhu, M. ; Yu, Q. ; Musielak, B. ; Wang, X. ; Awadasseid, A. ; Magiera-Mularz, K. (Corresponding author) ; Wu, Y. (Corresponding author) ; Zhang, W. (Corresponding author)

2023
ACS Washington, DC

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Please use a persistent id in citations: doi:10.1021/acs.jmedchem.3c00731

Abstract: Novel 2-arylmethoxy-4-(2,2′-dihalogen-substituted biphenyl-3-ylmethoxy) benzylamine derivatives were designed, synthesized, and evaluated in vitro and in vivo against cancers as PD-1/PD-L1 inhibitors. Through the computer-aided structural optimization and the homogeneous time-resolved fluorescence (HTRF) assay, compound A56 was found to most strongly block the PD-1/PD-L1 interaction with an IC50 value of 2.4 ± 0.8 nM and showed the most potent activity. 1H NMR titration results indicated that A56 can tightly bind to the PD-L1 protein with KD < 1 μM. The X-ray diffraction data for the cocrystal structure of the A56/PD-L1 complex (3.5 Å) deciphered a novel binding mode in detail, which can account for its most potent inhibitory activity. Cell-based assays further demonstrated the strong ability of A56 as an hPD-1/hPD-L1 blocker. Especially in an hPD-L1 MC38 humanized mouse model, A56 significantly inhibited tumor growth without obvious toxicity, with a TGI rate of 55.20% (50 mg/kg, i.g.). In conclusion, A56 is a promising clinical candidate worthy of further development.

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Contributing Institute(s):

1. DOOR-User (DOOR ; HAS-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)

Experiment(s):

1. PETRA Beamline P11 (PETRA III)

Appears in the scientific report 2023

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; Index Chemicus ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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