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. 2021 Feb 19;12(3):443-450.
doi: 10.1021/acsmedchemlett.0c00660. eCollection 2021 Mar 11.

Discovery of Orally Active Isofuranones as Potent, Selective Inhibitors of Hematopoetic Progenitor Kinase 1

Andrew P Degnan  1 , Godwin K Kumi  1 , Christopher W Allard  2 , Erika V Araujo  2 , Walter L Johnson  3 , Kurt Zimmermann  2 , Bradley C Pearce  2 , Steven Sheriff  1 , Alan Futran  1 , Xin Li  1 , Gregory A Locke  1 , Dan You  4 , John Morrison  1 , Karen E Parrish  1 , Caitlyn Stromko  1 , Anwar Murtaza  1 , Jinqi Liu  1 , Benjamin M Johnson  4 , Gregory D Vite  1 , Mark D Wittman  4
Affiliations

Discovery of Orally Active Isofuranones as Potent, Selective Inhibitors of Hematopoetic Progenitor Kinase 1

Andrew P Degnan et al. ACS Med Chem Lett. .

Abstract

While the discovery of immune checkpoint inhibitors has led to robust, durable responses in a range of cancers, many patients do not respond to currently available therapeutics. Therefore, an urgent need exists to identify alternative mechanisms to augment the immune-mediated clearance of tumors. Hematopoetic progenitor kinase 1 (HPK1) is a serine-threonine kinase that acts as a negative regulator of T-cell receptor (TCR) signaling, to dampen the immune response. Herein we describe the structure-based discovery of isofuranones as inhibitors of HPK1. Optimization of the chemotype led to improvements in potency, selectivity, plasma protein binding, and metabolic stability, culminating in the identification of compound 24. Oral administration of 24, in combination with an anti-PD1 antibody, demonstrated robust enhancement of anti-PD1 efficacy in a syngeneic tumor model of colorectal cancer.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Evolution of kinome mining hit 1 to isofuranone lead 3.
Figure 2
Figure 2
Docking of 2 and 3 into HPK1 homology model.
Figure 3
Figure 3
X-ray crystal structure of 24 bound to HPK1 (PDB: 7KAC).
Figure 4
Figure 4
Efficacy in the MC38 syngeneic tumor model. Compound 24 was administered orally (100 mg/kg twice daily) through day 28. Tumor volumes were monitored for 58 days.
Scheme 1
Scheme 1
Reagents and conditions: (a) 2-isopropenyl boronic acid pinacol ester, PdCl2(dppf)(CH2Cl2), K2CO3, 80 °C, 93%; (b) O2, Mn(dpm)3, PhSiH3, 0 °C then NaHCO3 in DMF/H2O, 85%; (c) DIEA, CH3CN, 84%; (d) 4 M HCl, NMP, 80 °C, 91%; (e) (i) NaOH, H2O/EtOH, 100%; (ii) R′RNH, BOP reagent, DIEA, DMF; (f) R(CNH)NHOH, NaOEt, 3 Å mol sieves, EtOH, 70 °C; (g) (i) hydrazine, EtOH, 70 °C, 99%; (ii) RCO2H, EDC, HOBt, DIEA, DMF, 40 °C then TsCl, TEA, 55 °C.
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