Hematopoietic progenitor kinase 1
(HPK1), a hematopoietic cell-restricted
member of the serine/threonine Ste20-related protein kinases, is a
negative regulator of the T cell receptor, B cell receptor, and
dendritic cells. Loss of HPK1 kinase function increases cytokine secretion
and enhances T cell signaling, virus clearance, and tumor growth
inhibition. Therefore, HPK1 is considered a promising target for tumor
immunotherapy. Several HPK1 inhibitors have been reported to regulate
T cell function. In addition, HPK1-targeting PROTACs, which can
induce the degradation of HPK1, have also been developed. Here, we
provide an overview of research concerning HPK1 protein structure,
function, and inhibitors and propose perspectives and insights for
the future development of agents targeting HPK1.
Stimulator of interferon gene (STING) is a critical adaptor
protein
that has a pivotal role in triggering inherent immune responses to
infection. STING-linked interferon production has been involved in
anti-inflammation, anti-infection, and antitumor immunity. Herein,
a series of amidobenzimidazole analogues as STING agonists were profiled
for potency and drug-like properties. By structure-based modification
and optimization based on mono-aminobenzimidazole (ABZI), analogues
with nanomolar STING agonistic activities were obtained. Among them,
compounds D59 and D61 significantly increased
the transcription of IFN-β and proinflammatory
cytokine CXCL10, as well as dramatically induced
the phosphorylation of STING downstream proteins in THP1 cells. Furthermore,
compound D61 exhibited favorable pharmacokinetic properties
and metabolic stabilities. In a CT-26 syngeneic mice-bearing tumor
model, D61 effectively inhibited tumor growth with good
tolerance when administered via intratumoral, intravenous, intraperitoneal,
and oral routes. This research on orally bioavailable amidobenzimidazole
analogues expands the diversity of chemical structures of agonists
for STING-mediated immunotherapy.
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