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HPK1 inhibitors and methods of using same

A CH2, -NH2 technology, applied in organic chemical methods, chemical instruments and methods, pharmaceutical formulations, etc., can solve problems such as cell death

Active Publication Date: 2018-04-17
UNIV HEALTH NETWORK
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Specifically, while full-length HPK1 promotes TCR-mediated activation of the nuclear factor-activated B-cell κ light chain enhancer (NF-κB) pathway, the catalytically inactive cleavage product, HPK1-C, inhibits NF-κB after TCR restimulation. -κB activation, leading to activation-induced cell death (AICD) (Brenner et al., EMBO J

Method used

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  • HPK1 inhibitors and methods of using same
  • HPK1 inhibitors and methods of using same
  • HPK1 inhibitors and methods of using same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment A

[0110] Example A: Synthesis

[0111] general method

[0112] Commercially available starting materials, reagents, and solvents were used as received. Generally, anhydrous reactions are performed under an inert atmosphere such as nitrogen or argon. Rxn CX refers to commercially available cation exchange resins available from Waters.

[0113]Microwave reactions were performed using a Biotage Initiator microwave reactor. Reaction progress was generally monitored by LCMS (Bruker Exquire 4000 or Waters Acquity UPLC system). Flash column chromatography purification of intermediates or final products was carried out using Biotage Isolera with KP-SIL or HP-SIL silica cartridges, or KP-NH basic modified silica and corresponding samplers (samplets) . Reverse-phase HPLC purification was carried out on a Varian PrepStar SD-1 HPLC system with a Varian Monochrom 10μC-18 reverse-phase column, using 10% MeOH / 0.05% TFA-H 2 O to H 2 A gradient of 90% MeOH / 0.05% TFA in O was performed ov...

Embodiment B

[0308] Example B: HPK1 Inhibition Assay

[0309] Active HPK1 (MAP4K1 ) was purchased from Invitrogen (cat#PV6355) as an N-terminal GST fusion of human HPK1 (aa 1-346). HPK1 activity was measured using an indirect ELISA detection system. GST-HPK1 (0.6nM) in the presence of 12μM ATP (Sigma cat#A7699), 5mM MOPS (pH 7.2), 2.5mM β-glycerol-phosphate, 5mM MgCl 2 , 0.4 mM EDTA, 1 mM EGTA, 0.05 mM DTT in 96-well microtiter plates pre-coated with 0.5 μg / well bovine myelin basic protein (MBP) (Millipore, cat#13-110). The reaction was carried out for 30 min, and then the plate was washed 5 times with washing buffer (phosphate-buffered saline supplemented with 0.2% Tween 20), and mixed with 1:1 of anti-phospho-threonine rabbit polyclonal antibody (Cell Signalingcat #9381). 3000 dilutions were incubated together for 30min. Plates were washed 5 times with wash buffer, incubated for 30 min in the presence of goat anti-rabbit horseradish peroxidase conjugate (BioRad cat#1721019, 1:3000 con...

Embodiment C

[0311] Example C: FLT3 Inhibition Assay

[0312] FLT3 and LCK compound inhibition was determined using a FRET-based Z'-LYTE Kinase Assay Kit with Tyrosine 2-peptide as substrate (Invitrogen cat #PV3191). The FLT3 kinase assay was performed at a concentration of 940 μM ATP and 1 nM FLT3 (Invitrogen cat #PV3182) following the manufacturer's suggested instructions, and 180 μM ATP and 25 nM LCK (Invitrogen cat #P3043) was used for the LCK kinase reaction. % inhibition values ​​are determined according to the manufacturer's guidelines, and the IC 50Values ​​were obtained using a nonlinear 4-point logistic curve fit (XLfit4, IDBS).

[0313] In Table 1 below, the ICs of exemplary compounds are given 50 range of values. IC 50 Ranges denote values ​​less than or equal to 0.05 μM; values ​​greater than 0.05 μM and less than or equal to 0.5 μM; and values ​​greater than 0.5 μM by “A”, “B” and “C”, respectively.

[0314] Table 1: Inhibition data of HPK1, Lck and Flt3

[0315]

[...

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Abstract

Thienopyridinone compounds of Formula (I) and pharmaceutically acceptable salts thereof are described. In these compounds, one of X1; X2, and X3 is S and the other two are each independently CR, wherein R and all other variables are as defined herein. The compounds are shown to inhibit HPK1 kinase activity and to have in vivo antitumor activity. The compounds can be effectively combined with pharmaceutically acceptable carriers and also with other immunomodulatory approaches, such as checkpoint inhibition or inhibitors of tryptophan oxidation.

Description

[0001] related application [0002] This application claims the benefit of US Provisional Application No. 62 / 184,348, filed June 25, 2015. The entire teachings of the aforementioned applications are incorporated herein by reference. Background technique [0003] Hematopoietic progenitor kinase 1 (HPK1) is a hematopoietic cell-restricted Ste20 serine / threonine kinase. HPK1 kinase activity can be induced upon ligand engagement by activation signals generated by various cell surface receptors found in hematopoietic cells. T cell receptor (TCR), B cell antigen receptor (BCR) (Liou et al., 2000, Immunity 12:399), transforming growth factor β receptor (TGF-βR) (Wang et al., 1997.J .Biol.Chem.272:22771; Zhou et al., 1999, J.Biol.Chem.274:13133), erythropoietin receptor (EPOR) (Nagata et al., 1999, Blood 93:3347), Ligand conjugation or antibody-mediated cross-linking with Fas (Chen et al., 1999, Oncogene 18:7370) induces HPK1 kinase activity. Each receptor activates HPK1 using uni...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04A61K31/4436A61K31/444A61K31/4545A61K31/496A61K31/551A61K39/395A61P35/00
CPCC07D495/04A61P35/00C07B2200/07A61K31/4355A61K31/4365A61K31/444A61K31/4545A61K31/496A61K31/5355A61K31/5377A61K31/551A61K39/395A61K45/06A61K2039/505A61K2300/00C07K16/2818
Inventor P·B·桑普森N·K·B·帕特尔H·W·鲍尔斯李诗韵G·恩格R·劳弗刘勇郎云辉
Owner UNIV HEALTH NETWORK
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