Delving into the Latest Updates on ZYF-0033 with Synapse

Overview

Basic Info

Drug Type

Proteolysis-targeting chimeras (PROTAC)

Synonyms

Target

HPK1

Action

inhibitors

Mechanism

HPK1 inhibitors(Mitogen-activated protein kinase kinase kinase kinase 1 inhibitors)

Therapeutic Areas

Neoplasms

Active Indication

Neoplasms

Inactive Indication-

Originator Organization

Tsinghua University

Active Organization

Tsinghua University

Inactive Organization-

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC26H30N4O2S

InChIKeyBJNWUKRWOQERPQ-UHFFFAOYSA-N

CAS Registry2380300-79-6

Author: Liu, Tian ; Gao, Guangxun ; Wei, Lai ; Pang, Bo ; Li, Yaopeng ; Chi, Wenna ; Liu, Xing ; Si, Jingwen ; An, Dongjie ; Long, Fei ; Sun, Shuhao ; Shi, Xiangjun ; Yin, Wen ; Lin, Xingyu ; Liao, Xuebin ; Sun, Yan ; Min, Junxia ; Gao, Yan ; Du, Xinru ; Dimitrov, Dimiter S ; Zou, Bin ; Chen, Ligong

Ameliorating T cell exhaustion and enhancing effector function are promising strategies for the improvement of immunotherapies. Here, we show that the HPK1-NFκB-Blimp1 axis mediates T cell dysfunction. High expression of MAP4K1 (which encodes HPK1) correlates with increased T cell exhaustion and with worse patient survival in several cancer types. In MAP4K1^KO mice, tumors grow slower than in wild-type mice and infiltrating T cells are less exhausted and more active and proliferative. We further show that genetic depletion, pharmacological inhibition, or proteolysis targeting chimera (PROTAC)-mediated degradation of HPK1 improves the efficacy of CAR-T cell-based immunotherapies in diverse preclinical mouse models of hematological and solid tumors. These strategies are more effective than genetically depleting PD-1 in CAR-T cells. Thus, we demonstrate that HPK1 is a mediator of T cell dysfunction and an attractive druggable target to improve immune therapy responses.

100 Deals associated with ZYF-0033

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