Discovery of an Exceptionally Orally Bioavailable and Potent HPK1 PROTAC with Enhancement of Antitumor Efficacy of Anti-PD-L1 Therapy.
J Med Chem
; 67(16): 13852-13878, 2024 Aug 22.
Article
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| MEDLINE
| ID: mdl-39084610
ABSTRACT
HPK1, a well-known negative regulator of T cell receptors, can cause T cell dysfunction when abnormally activated. In this study, a PROTAC C3 was designed and synthesized by optimizing the physicochemical properties of the warhead, linker, and CRBN ligand. C3 demonstrated significant HPK1 degradation with a DC50 of 21.26 nM, excellent oral absorption with a Cmax of 10,899.92 ng/mL, and a bioavailability (F %) of 81.7%. C3 also showed degradation selectivity and potent immune activation effects. Proteomic and WB analyses revealed that immune-activating effect of C3 is attributed to the inhibition of SLP76 and NF-κB signaling pathways, as well as the enhancement of MAPK signaling pathway transduction. In vivo efficacy study demonstrated that oral administration of C3 in combination with anti-PDL1 antibody significantly inhibited tumor growth (tumor growth inhibition = 65.58%). These findings suggest that C3, a novel HPK1 PROTAC, holds promise as a therapeutic agent for tumor immunotherapy.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Proteínas Serina-Treonina Quinasas
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Antígeno B7-H1
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Antineoplásicos
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2024
Tipo del documento:
Article