Design, Synthesis, and Pharmacological Evaluation of Isoindoline Analogues as New HPK1 Inhibitors

Hematopoietic progenitor kinase 1
(HPK1) is an important
negative
regulator in T-cell receptor signaling and as a promising key target
for immunotherapy. Herein, based on the reported HPK1 inhibitor 2 featuring an isofuranone component, a structural optimization
approach was conducted leading to several series of derivatives characterized
by containing an isoindoline structural motif. Compound 49 was identified as a new potent HPK1 inhibitor with an IC50 value of 0.9 nM, more potent than compound 2 (5.5 nM).
It also has an improved IV profile in rats and enhanced aqueous solubility.
It effectively inhibited pSLP76 and reinvigorated T-cell receptor
(TCR) signaling, promoting T-cell function and cytokine production
both in naïve and antigen-specific T cells. Furthermore, compound 49 reversed the inhibition on T-cell activity mediated by
classic immunosuppressive factors in the tumor microenvironment (TME).
In the murine CT-26 tumor model, this compound reinvigorated the T
cell and synergistically enhanced the antitumor efficacy of anti-PD1
at a well-tolerant dosage.