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Structure-Based Discovery of Potent CARM1 Inhibitors for Solid Tumor and Cancer Immunology Therapy.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2021 Nov 25; Vol. 64 (22), pp. 16650-16674. Date of Electronic Publication: 2021 Nov 15. - Publication Year :
- 2021
-
Abstract
- CARM1 is a protein arginine methyltransferase and acts as a transcriptional coactivator regulating multiple biological processes. Aberrant expression of CARM1 has been related to the progression of multiple types of cancers, and therefore CARM1 was considered as a promising drug target. In the present work, we report the structure-based discovery of a series of N <superscript>1</superscript> -(3-(pyrimidin-2-yl)benzyl)ethane-1,2-diamines as potent CARM1 inhibitors, in which compound 43 displays high potency and selectivity. With the advantage of excellent tissue distribution, compound 43 demonstrated good in vivo efficacy for solid tumors. Furthermore, from the detailed immuno-oncology study with MC38 C57BL/6J xenograft model, we confirmed that this chemical probe 43 has profound effects in tumor immunity, which paves the way for future studies on the modulation of arginine post-translational modification that could be utilized in solid tumor treatment and cancer immunotherapy.
- Subjects :
- Animals
Antineoplastic Agents chemistry
CARD Signaling Adaptor Proteins metabolism
Guanylate Cyclase metabolism
Humans
Mice
Mice, Inbred C57BL
Neoplasms immunology
Protein Processing, Post-Translational
Structure-Activity Relationship
Xenograft Model Antitumor Assays
Antineoplastic Agents pharmacology
CARD Signaling Adaptor Proteins antagonists & inhibitors
Drug Discovery
Guanylate Cyclase antagonists & inhibitors
Immunotherapy methods
Neoplasms therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 64
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 34781683
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.1c01308