Uses
HPK1-IN-7 is a potent, orally active HPK1 (hematopoietic progenitor kinase 1, MAP4K1) inhibitor (IC50=2.6 nM) with excellent family and kinome selectivity. HPK1-IN-7 shows selectivity against IRAK4 (59 nM) and GLK (140 nM). HPK1-IN-7 shows robust efficacy against MC38 syngeneic tumor model in combination with anti-PD1[1].
in vivo
HPK1-IN-7 (100 mg/kg; p.o.; twice daily for 28 days) shows robust enhancement of anti-PD1 efficacy in a syngeneic tumor model of colorectal cancer[1].
HPK1-IN-7 (compound 24) (1 mg/kg; intravenous; mice) is characterized by moderate plasma clearance (43 mL/min/kg) and a large volume of distribution (4.4 L/kg). After oral administration (20 mg/kg), the Cmax was 5.3 μM and the AUC0-24h was 19 μMh. The calculated oral bioavailability based on these pharmacokinetics studies is approximately 100%[1].
| Animal Model: | Mice (MC38 syngeneic tumor model)[1] |
| Dosage: | 100 mg/kg |
| Administration: | Oral; twice daily for 28 days |
| Result: | Enhanced the efficacy of anti-PD1 treatment, garnering a 100% cure rate vs a 20% cure rate with anti-PD1 alone. |
IC 50
HPK1: 2.6 nM (IC
50); GLK/MAP4K3: 140 nM (IC
50); IRAK4: 59 nM (IC
50); Fms/CSFR: 3.2 nM (IC
50); FLT3: 25.4 nM (IC
50); AMPKA1: 44.3 nM (IC
50); cKIT: 45.7 nM (IC
50); MST1: 55.1 nM (IC
50); ICK: 65.1 nM (IC
50); MST2: 78.5 nM (IC
50)
References
[1] Degnan AP, et al. Discovery of Orally Active Isofuranones as Potent, Selective Inhibitors of Hematopoetic Progenitor Kinase 1. ACS Med Chem Lett. 2021;12(3):443-450. Published 2021 Feb 19. DOI:
10.1021/acsmedchemlett.0c00660
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