LCP2 (Lymphocyte cytosolic protein 2)

Notably, D02 exhibited favorable safety profiles in preliminary toxicological evaluations. We propose that D02 represents a promising candidate for further development of HPK1 degraders.

Furthermore, oral dosing of compound 34 combined with anti-PD-1 achieved significant anti-tumor effect (TGI = 62.90 %) in the CT-26 syngeneic model. These findings demonstrated compound 34 as a promising preclinical candidate worthy of further investigation.

Mechanistically, MT-SLP-76 amplifies CAR signaling through recruitment of ITK and PLCγ1. MT-SLP-76 was designed based on biologic principles to render CAR T cell therapies less susceptible to antigen downregulation and is poised for clinical development to overcome this common mechanism of resistance.

This enhanced phosphorylation of CD3ζ, ZAP70, and SLP-76 which augmented secretion of IFN-γ and TNF-α, by NK cells from healthy donors and AML patients. Thus, in addition to connecting immune cells to target cells, the clinical promise of engagers results from their ability to manipulate the nanoscale architecture of the immune synapse.

Moreover, 10m achieved a superior antitumor effect when combined with PD-1 blockade, suggesting the complementarity between the two treatment modalities. Overall, this work provides promising lead compounds for the clinical development of HPK1 PROTACs as small-molecule therapeutics in tumor immunotherapy.

HPK1 deficiency, caused by heterozygous loss of MAP4K1, is a novel monogenic cause of immune dysregulation. Increased T cell activation and pro-inflammatory cytokine production are implicated in disease pathogenesis.

Furthermore, compound 21 effectively inhibited phosphorylation of the downstream adaptor protein SLP76 and enhanced IL-2 secretion in human Jurkat T cells. Taken together, this study further validates macrocyclization as an effective strategy for designing HPK1 inhibitors with innovative scaffolds and offers compound 21 as a structurally novel lead compound for the development of HPK1 inhibitors.

Additionally, it markedly inhibits the phosphorylation of the downstream adaptor protein SLP76, with an IC50 of 33.74 nM, and effectively stimulates the secretion of the T cell activation marker IL-2, exhibiting an EC50 of 84.24 nM. These findings suggest that compound 10c holds considerable promise for applications in immunotherapy.

Thus, FGR triggers signaling events and phenotypic shifts characteristic of RA. This finding represents a paradigm shift, given FGR's historical role as a pro-proliferation oncogene.

Notably, compound 24 exhibited enhanced potency in promoting IL-2 secretion in Jurkat T cells, reduced cellular toxicity, and improved liver microsomal stability compared to hit 9. Overall, this study provides a promising lead compound for further optimization as a candidate for cancer immunotherapy.

Furthermore, A29 was efficacious in a CT26 xenograft mouse model alone, and significantly enhanced the antitumor efficacy of an anti-PD-1 antibody. This work provides a promising lead for the development of effective HPK1 inhibitors for tumor immunotherapy.

Furthermore, DD205-291 exhibited a low risk of cardiotoxicity and a wide safety window. This research effort demonstrates that DD205-291 is a promising preclinical candidate (PCC) for potential mono- and comboimmunotherapy of cancer.