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Discovery of Novel PROTAC-Based HPK1 Degraders with High Potency and Selectivity for Cancer Immunotherapy

Zhimin Zhang1, Liubin Guo1, Mengting Zhao1

  • 1Global Drug R&D Center, Huadong Medicine, Hangzhou 310011, P. R. China.

Journal of Medicinal Chemistry
|October 24, 2024
PubMed

Insights

A novel compound, DD205-291, effectively degrades Hematopoietic progenitor kinase 1 (HPK1) to boost anti-cancer immune responses. This potent degrader shows promise for cancer immunotherapy, enhancing T-cell activity and tumor suppression.

Area of Science:

  • Immunology
  • Oncology
  • Pharmacology

Background:

  • Hematopoietic progenitor kinase 1 (HPK1) negatively regulates T-cell receptor signaling, making it a target for cancer immunotherapy.
  • Inhibiting HPK1 function can suppress tumor growth, offering a therapeutic strategy.

Purpose of the Study:

  • To introduce a novel PROTAC-based HPK1 degrader, DD205-291, with high selectivity and potency.
  • To evaluate the efficacy and safety profile of DD205-291 in preclinical cancer models.

Main Methods:

  • Development of a PROTAC-based compound targeting HPK1.
  • Assessment of DD205-291's effect on T-cell signaling, cytokine production (IL-2, IFN-γ), and tumor growth inhibition (TGI).
  • Evaluation of safety and cardiotoxicity in the MC38 tumor model.

Main Results:

  • DD205-291 demonstrated dose-dependent inhibition of SLP-76 phosphorylation and induced IL-2 and IFN-γ.
  • Oral administration of DD205-291 (0.5 mg/kg) combined with anti-PD1 therapy achieved 91.0% tumor growth suppression.
  • The compound exhibited a favorable safety profile with low cardiotoxicity risk and a wide safety window.

Conclusions:

  • DD205-291 is a potent and selective HPK1 degrader with significant anti-tumor efficacy.
  • DD205-291 represents a promising preclinical candidate for both monotherapy and combination immunotherapy in cancer treatment.

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