Pyrrolo[2,3-d]pyrimidines as potential kinase inhibitors in cancer drug discovery: A critical review

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 153, P. 107867 - 107867

Published: Oct. 4, 2024

Language: Английский

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Discovery of GNE-6893, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of HPK1

ACS Medicinal Chemistry Letters, Journal Year: 2024, Volume and Issue: 15(9), P. 1606 - 1614

Published: Sept. 3, 2024

Hematopoietic progenitor kinase 1 (HPK1) serves a key immunosuppressive role as negative regulator of T-cell receptor (TCR) signaling. HPK1 loss-of-function is associated with augmentation immune function and has demonstrated synergy checkpoint inhibitors in syngeneic mouse cancer models. These data offer compelling evidence for the use selective small molecule immunotherapy. We identified novel series isoquinoline through fragment-based screening that displayed promising levels biochemical potency activity functional cell-based assays. used structure-based drug design to introduce selectivity elements while simultaneously addressing pharmacokinetic liabilities. efforts culminated demonstrating subnanomolar inhibition strong

Language: Английский

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Discovery of Pyridine-2-Carboxamides Derivatives as Potent and Selective HPK1 Inhibitors for the Treatment of Cancer

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 25, 2024

Hematopoietic progenitor kinase 1 (HPK1) has emerged as an attractive target for immunotherapy due to its critical role in T cell activation and proliferation. The major challenge developing HPK1 inhibitors lies balancing selectivity, pharmacokinetic (PK) properties, therapeutic efficacy. In this study, we report a series of pyridine-2-carboxamide analogues demonstrating strong inhibitory activity enzymatic cellular assays, along with good selectivity. Among these analogues, compound

Language: Английский

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Discovery of Novel PROTAC-Based HPK1 Degraders with High Potency and Selectivity for Cancer Immunotherapy

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(21), P. 18682 - 18698

Published: Oct. 24, 2024

Hematopoietic progenitor kinase 1 (HPK1, MAP4K1), a serine/threonine (SER/THR) kinase, has been identified as negative immune regulator of T-cell receptor signaling. Deprivation the HPK1 function suppresses tumor growth, providing an attractive strategy for cancer immunotherapy. Herein, we present novel PROTAC-based degrader compound DD205-291 with high selectivity and potency. showed dose-dependent inhibition SLP-76 phosphorylation induction IL-2 IFN-γ. Compared other inhibitors, exhibited good efficacy favorable safety profile in MC38 model. Specifically, oral administration at 0.5 mg/kg combination anti-PD1 resulted significant suppression TGI value 91.0%. Furthermore, low risk cardiotoxicity wide window. This research effort demonstrates that is promising preclinical candidate (PCC) potential mono- comboimmunotherapy cancer.

Language: Английский

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Design, Synthesis, and Biological Evaluation of a Series of Spiro Analogues as Novel HPK1 Inhibitors

ACS Medicinal Chemistry Letters, Journal Year: 2024, Volume and Issue: 15(11), P. 2032 - 2041

Published: Oct. 30, 2024

Hematopoietic progenitor kinase 1 (HPK1) negatively affects T cell activation and proliferation is a promising target for immunotherapy. Although HPK1 inhibitors have shown efficacy in preclinical models, none been approved clinical use. One significant challenge developing an inhibitor the difficulty designing potent with good selectivity pharmacokinetic properties. Here, we report series of spiro potency selectivity. Specifically, compound

Language: Английский

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An Oral PROTAC Targeting HPK1 Degradation Potentiates Anti‐Solid Tumor Immunity

Advanced Materials, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 20, 2024

Abstract Hematopoietic progenitor pinase1 (HPK1) knockout has been identified as an efficient route to enhance anti‐tumor immune response. Here, this work develops oral proteolysis targeting chimera (PROTAC) HPK1 efficiently and selectively degrade augment immunotherapeutic outcomes. In a postoperative tumor model of human cervical cancer in NSG mice, the orally‐administrated PROTAC can reach tumors, down‐regulate levels locally‐administrated CAR‐T cells, promote their efficiency inhibiting solid recurrence, achieving 50% partial response (PR) complete (CR). addition, administration amplify suppression capability anti‐PD‐L1 antibody on growth CT26 tumors BALB/c mice by promoting infiltration CD45‐positive cells from 0.7% 1.5% CD3‐positive T 0.2% 0.5% within tumors.

Language: Английский

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An updated review of small-molecule HPK1 kinase inhibitors (2016-present)

Future Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 20

Published: Nov. 25, 2024

Hematopoietic progenitor kinase 1 (HPK1) is a serine-threonine specific to hematopoiesis and member of the MAP4K family Ste20-related protein kinases. Targeting HPK1 ameliorate T cell exhaustion enhance functions promising strategy for clinical immunotherapies. Numerous studies have reported progress in developing effective inhibitors elucidating their mechanisms action. However, most affect multiple signaling pathways, resulting unintended side effects that limit development application. Herein, we reviewed HPK1-related candidates recent advances small-molecule targeting HPK1. Additionally, present our perspectives on current challenges potential future research field, hoping provide inspiration novel inhibitors.

Language: Английский

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Opportunities and challenges for targeting HPK1 in cancer immunotherapy

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 153, P. 107866 - 107866

Published: Oct. 4, 2024

Language: Английский

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