BGB-15025, a potent and selectiveHPK1 inhibitor, is efficacious as asingle agent or in combination withPD-1 antibody in multiple tumormodels
20220316

BGB-15025, a potent and selective HPK1 inhibitor, is efficacious as a single agent or in combination with PD-1 antibody
in multiple tumor models
Ye Liu1#, Jing Li2#, Zhuo Li1, Qin Wang1, Xing Zhou1, Xiaoxin Liu1, Bo Zhang1, Xitao Wang1, Sanjia Xu2, Hanzi Sun1, Xiaomin Song1, Xi Yuan1, Zhiwei Wang2,Xuesong Mike Liu1*
Department of Biology1 and Chemistry2, BeiGene (Beijing) Co., Ltd., Beijing 102206, P.R.China; * Correspondence: Mike.Liu@beigene.com# Contribute equally to this work.

Abstract:
Hematopoietic progenitor kinase 1 (HPK1), a hematopoietic cell-restricted serine/threonine protein kinase, has been reported to serve as a critical negative
feedback regulator of T lymphocytes by phosphorylating the adaptor protein SLP76 in the TCR complex. The negative feedback role of HPK1 in TCR
signaling makes it a promising target for immuno-oncology therapy. It has been recently demonstrated that the kinase activity of HPK1 is essential for its
antitumor activity, and HPK1 inhibitors can be potentially combined with immune checkpoint inhibitor therapy (such as PD-1 antibody) for effective cancer
treatment.
Here, we report a potent and selective HPK1 inhibitor BGB-15025 which has been identified through in-house high throughput screening and structureguided drug design. BGB-15025 potently inhibits HPK1 kinase activity in biochemical assay, with a 50% inhibitory concentration (IC50) of 1.04 nM under Kmconcentration of ATP. Consistently, BGB-15025 can potently reduce SLP76 phosphorylation and increase downstream ERK phosphorylation in aconcentration dependent manner in T cells-based assay. As a consequence, BGB-15025 induces TCR activation and IL-2 production in T cells. Owning to thefunction diversity and high sequence homology among MAP4K family members, it is difficult to develop a selectivity HPK1 inhibitor and spare otherMAP4Ks. Based on inhouse profiling, BGB-15025 shows good selectivity profile against other MAP4K family members. Oral administration of BGB-15025
demonstrates dose-dependent pSLP76 inhibition in splenic T cells and induces serum IL-2 in mouse model. In efficacy studies, BGB-15025 demonstrated
combination effect with anti-PD-1 antibody in CT26 and EMT-6 syngeneic tumor models. BGB-15025 is currently in phase I clinical trial to treat patientswith advanced solid tumor , both as a single agent and in combination with anti PD-1 antibody tislelizumab.

2

BGB-15025 is a potent and specific HPK1 kinase inhibitor
HPK1 kinasedomainBGB-15025

KinaseIC50(nM) of BGB-15025

Assay condition

MAP4K1(HPK1)

1.04

Km ATP

MAP4K1(HPK1)

62

1mM ATPMAP4K2(GCK)>100001mM ATPMAP4K3(GLK)5520

1mM ATPMAP4K4(HGK)>100001mM ATPMAP4K5(KHS)362

1mM ATPMAP4K6(MINK1)>100001mM ATP

Co-crystal structure of BGB-15025 in complex with HPK1 kinase domain.

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BGB-15025 potently inhibits pSLP76 and activates T cell in vitro

Cells
Jurkat Cells
PBMC

Stimulation
anti-CD3
anti-CD3
anti-CD3 plus antiCD28

pSLP76
IL-2

IC50/EC50 (nM)
Mean ± StandardDeviation
150 ± 14267 ± 39IL-2261 ± 64

Molecule
Measured

Fold IncreasenN/A
5.4 ± 0.6334.3 ± 1.734

BGB-15025 has a good selectivity to HPK1 over other proximal
components of the TCR complex

BGB-15025 inhibited SLP76 phosphorylation andincreased ERK phosphorylation but not affect
ZAP70 phosphorylation up to 1 μM.

5Dose-dependent in vivo pSLP76 inhibition and IL2 production
induced by BGB-15025*********

10*** ***

an icletiCD32hr4hr6hr2hr4hr6hr2hr4hr6hr0+ 1mg/kg+ 3mg/kg+ 10mg/kg

30*20**********

10*** ***0an icletiCD
32hr4hr6hr2hr4hr6hr2hr4hr6hr

**

40Veh

*

CD8+pSLP76+/CD8+,%

20VehCD4+pSLP76+/CD4+,%30+ 1mg/kg+ 3mg/kg+ 10mg/kg

6BGB-15025 shows anti-tumor efficacy in CT-26WT model assingle agent and combo with anti-PD1**p < 0.01 calculated by EOHSA criterion

Efficacy of the combination of BGB-15025 and anti-PD1 in syngeneic CT26WT model in BALB/c mice.

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BGB-15025 and anti-PD1 shows significant combo anti-tumor
efficacy in EMT-6 model
EFC-EMT6-2102 BW*

Mean Body Weight (g±SEM)

Mean Tumor Volume (mm3 ± SEM)

BGB-15025 30 mg/kg
2000
1500
1000
50000510152025Treatment Days
TGI% vs Vehicle TF 0<TV<50mm3on T25Vehicle p.o. BID
on T25on T25
38
30Ch15mt 3 mg/kg
2160
BGB-15025 30mg/kg BID
BGB-15025 30mg/kg BID + CH15mt

71625201510500

5

10

15

20

25

Treatment Days2

* p< 0.05 calculated by EOHSA criterion8