Compound 21(UIOWA)

Hematopoietic progenitor kinase 1 (HPK1) functions as a key negative regulator of T cell receptor signaling and has been considered a potential target for cancer immunotherapy. Despite great progress in developing HPK1 inhibitors, no small-molecule inhibitors have been approved for cancer treatment to date. Herein, we describe the design and synthesis of a novel series of macrocyclic 2,4-diaminopyrimidine derivatives as HPK1 inhibitors. Among these, the representative compound 21 exhibited potent HPK1 inhibition with an IC₅₀ value of 1.0 nM in an ADP-Glo assay. 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.

Women with a history of preeclampsia (hxPE) have a ≥4-fold risk for developing cardiovascular disease (CVD) compared with women who had a healthy pregnancy (hxHC). HxPE have exaggerated vasoconstrictor sensitivity to angiotensin (ang) II after pregnancy, which likely contributes to CVD progression after preeclampsia. Ang II-mediated constriction via ang II type 1 receptors (AT1R) is countered by vasodilatory ang II type 2 receptors (AT2R); however, the extent to which reductions in AT2R-mediated responses contribute to exaggerated ang II-mediated constriction after preeclampsia remains unknown. We examined the balance of AT1R- and AT2R-mediated responses in hxPE and hxHC (n=12/group). We hypothesized that (1) attenuated AT2R-mediated dilation would be improved with AT1R inhibition in hxPE, and (2) AT2R inhibition would increase ang II-mediated constriction in hxHC but have no effect in hxPE. We measured cutaneous vascular conductance responses to compound 21 (AT2R agonist; 10-14–10-8mol/L) alone or with losartan (AT1R antagonist; 43 μmol/L) to assess AT2R-mediated dilation, and ang II (10−20–10−4 mol/L) alone or with PD-123319 (AT2R antagonist; 1 μmol/L) to assess the role of AT2R in vasoconstrictor sensitivity to ang II. Reduced AT2R-mediated dilation in hxPE (P=0.002) was improved with AT1R inhibition (P<0.001). Vasoconstrictor sensitivity to ang II was greater in hxPE compared with hxHC (P<0.001). Circulating AT1R agonistic autoantibodies (AT1-AA) were elevated in hxPE (P=0.015). AT2R inhibition increased the vasoconstrictor response to ang II in hxHC (P<0.001) but had no effect in hxPE (P=0.19). These data suggest that hxPE has reduced AT2R-mediated dilation that contributes to increased ang II vasoconstrictor sensitivity after preeclampsia.