Discovery of a Novel CSF-1R Inhibitor with Highly Improved Pharmacokinetic Profiles and Superior Efficacy in Colorectal Cancer Immunotherapy.
J Med Chem
; 67(8): 6854-6879, 2024 Apr 25.
Article
en En
| MEDLINE
| ID: mdl-38593344
ABSTRACT
Blocking CSF-1/CSF-1R pathway has emerged as a promising strategy to remodel tumor immune microenvironment (TME) by reprogramming tumor-associated macrophages (TAMs). In this work, a novel CSF-1R inhibitor C19 with a highly improved pharmacokinetic profile and in vivo anticolorectal cancer (CRC) efficiency was successfully discovered. C19 could effectively reprogram M2-like TAMs to M1 phenotype and reshape the TME by inducing the recruitment of CD8+ T cells into tumors and reducing the infiltration of immunosuppressive Tregs/MDSCs. Deeper mechanistic studies revealed that C19 facilitated the infiltration of CD8+ T cells by enhancing the secretion of chemokine CXCL9, thus significantly potentiating the anti-CRC efficiency of PD-1 blockade. More importantly, C19 combined with PD-1 mAb could induce durable antitumor immune memory, effectively overcoming the recurrence of CRC. Taken together, our findings suggest that C19 is a promising therapeutic option for sensitizing CRC to anti-PD-1 therapy.
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1
Base de datos:
MEDLINE
Asunto principal:
Neoplasias Colorrectales
/
Receptor de Factor Estimulante de Colonias de Macrófagos
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Inmunoterapia
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2024
Tipo del documento:
Article