Delving into the Latest Updates on HRS-4642 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

KRAS G12D

Mechanism

KRAS G12D inhibitors(GTPase KRas G12D inhibitors)

Therapeutic Areas

NeoplasmsDigestive System DisordersEndocrinology and Metabolic Disease

Active Indication

Pancreatic CancerKRAS G12D mutation Solid TumorsAdvanced Malignant Solid Neoplasm

Inactive Indication-

Originator Organization

Jiangsu Hengrui Pharmaceuticals Co., Ltd.

Active Organization

Jiangsu Hengrui Pharmaceuticals Co., Ltd.

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Author: Jia, Keyi ; Huang, Kan ; He, Feng ; Chen, Yingxue ; Yu, Yaxin ; Mao, Shiqi ; Sun, Xing ; Ren, Shengxiang ; Wang, Zaiyong ; Mao, Rongfu ; Jiang, Tao ; Zhang, Zhe ; Yu, Jia ; Liu, Xinyu ; Cai, Xinlei ; Shi, Wei ; Shao, Chuchu ; Li, Xin ; Li, Wei ; Dai, Zican ; Luo, Libo ; Li, Chongyang ; Shen, Feng ; He, Ning ; Zhou, Caicun ; Zhang, Jun ; Wang, Wanying ; Li, Fei ; Li, Jiayu

KRAS G12D is the most frequently mutated oncogenic KRAS subtype in solid tumors and remains undruggable in clinical settings. Here, we developed a high affinity, selective, long-acting, and non-covalent KRAS G12D inhibitor, HRS-4642, with an affinity constant of 0.083 nM. HRS-4642 demonstrated robust efficacy against KRAS G12D-mutant cancers both in vitro and in vivo. Importantly, in a phase 1 clinical trial, HRS-4642 exhibited promising anti-tumor activity in the escalating dosing cohorts. Furthermore, the sensitization and resistance spectrum for HRS-4642 was deciphered through genome-wide CRISPR-Cas9 screening, which unveiled proteasome as a sensitization target. We further observed that the proteasome inhibitor, carfilzomib, improved the anti-tumor efficacy of HRS-4642. Additionally, HRS-4642, either as a single agent or in combination with carfilzomib, reshaped the tumor microenvironment toward an immune-permissive one. In summary, this study provides potential therapies for patients with KRAS G12D-mutant cancers, for whom effective treatments are currently lacking.

01 Jul 2024·Cancer Cell

HRS-4642: The next piece of the puzzle to keep KRAS in check

Article

Author: Drosten, Matthias ; Flores-Gómez, Alejandra A

KRAS^G12D is the most frequent KRAS mutation in human cancer. In this issue, Zhou et al. describe a novel KRAS^G12D inhibitor, HRS-4642, that shows potent and selective anti-tumor activity across various models and synergizes with proteasome inhibitors. Responses have also been observed in patients during an ongoing phase 1 trial.

12 Dec 2023·Cancer Discovery

Drugging RAS: Moving Beyond KRASG12C

Article

AbstractPreliminary results from phase I trials respectively evaluating RMC-6236, a pan-RAS inhibitor, and HRS-4642, a KRASG12D inhibitor, indicate that both are safe and show promising signs of antitumor activity. These are just two of the candidate RAS therapies in a burgeoning development space as the field looks ahead to drugs that hit more than just KRASG12C.

100 Deals associated with HRS-4642

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Pancreatic Cancer	Phase 2	CN	Jiangsu Hengrui Pharmaceuticals Co., Ltd.	01 Oct 2024
KRAS G12D mutation Solid Tumors	Phase 2	CN	Jiangsu Hengrui Pharmaceuticals Co., Ltd.	05 Jul 2024
Advanced Malignant Solid Neoplasm	Phase 2	CN	Jiangsu Hengrui Pharmaceuticals Co., Ltd.	01 Jul 2024

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05533463 (ESMO2023) Manual	Phase 1	KRAS G12D mutation Solid Tumors KRAS G12D	18	HRS-4642 (advanced solid tumors harboring KRAS G12D mutation)	(plmgvmfzym) = fevwoswwqb aikvaqqkhb (gcjzabmrwj ) View more	Positive	22 Oct 2023