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. 2021 Dec 8;13(1):84-91.
doi: 10.1021/acsmedchemlett.1c00473. eCollection 2022 Jan 13.

Discovery of Spiro-azaindoline Inhibitors of Hematopoietic Progenitor Kinase 1 (HPK1)

Bryan K Chan  1 , Eileen Seward  2 , Michael Lainchbury  2 , Thomas F Brewer  1 , Le An  1 , Toby Blench  2 , Matthew W Cartwright  2 , Grace Ka Yan Chan  1 , Edna F Choo  1 , Jason Drummond  1 , Richard L Elliott  2 , Emanuela Gancia  2 , Lewis Gazzard  1 , Baihua Hu  3 , Graham E Jones  2 , Xifeng Luo  3 , Andrew Madin  2 , Sushant Malhotra  1 , John G Moffat  1 , Jodie Pang  1 , Laurent Salphati  1 , Christopher J Sneeringer  1 , Craig E Stivala  1 , Binqing Wei  1 , Weiru Wang  1 , Ping Wu  1 , Timothy P Heffron  1
Affiliations

Discovery of Spiro-azaindoline Inhibitors of Hematopoietic Progenitor Kinase 1 (HPK1)

Bryan K Chan et al. ACS Med Chem Lett. .

Abstract

Hematopoietic progenitor kinase 1 (HPK1) is implicated as a negative regulator of T-cell receptor-induced T-cell activation. Studies using HPK1 kinase-dead knock-in animals have demonstrated the loss of HPK1 kinase activity resulted in an increase in T-cell function and tumor growth inhibition in glioma models. Herein, we describe the discovery of a series of small molecule inhibitors of HPK1. Using a structure-based drug design approach, the kinase selectivity of the molecules was significantly improved by inducing and stabilizing an unusual P-loop folded binding mode. The metabolic liabilities of the initial 7-azaindole high-throughput screening hit were mitigated by addressing a key metabolic soft spot along with physicochemical property-based optimization. The resulting spiro-azaindoline HPK1 inhibitors demonstrated improved in vitro ADME properties and the ability to induce cytokine production in primary human T-cells.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
(A) X-ray structure of 3 bound in HPK1 (PDB: 7R9L) and (B) X-ray structure of G1858 bound in HPK1 (PDB: 7R9N). Predicted hydrogen bond interactions are shown as dashed lines. Distances from N/O to hydrogen are shown.
Figure 2
Figure 2
X-ray structures of (A) 14 (PDB: 7R9P) and (B) 17 (PDB: 7R9T) bound to HPK1. Red circles represent water molecules. Predicted hydrogen bonds: Interactions are shown as dashed lines; distances from N/O to hydrogen are shown. Pink arrow represents the distance between the carbons labeled with asterisks.
Figure 3
Figure 3
Dose–response curve measuring IL2 levels in human pan T-cell cultures after treatment with 25 followed by stimulation with αCD3 and αCD28 (calculated EC50 = 1.56 ± 0.10 μM). Activity displayed as percent increase in IL2 concentration relative to stimulated/untreated controls. Data points represent results from two replicates.
Scheme 1
Scheme 1. Synthesis of Compound 25
See this image and copyright information in PMC

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