Jinfang Pharmaceutical Co., Ltd. KRAS G12C inhibitor GFH925 is applied for clinical application, and many companies such as Amgen, Novartis, Betta Pharmaceutical Co., Ltd. are deployed

On May 26, according to the official website of CDE Jinfang Pharmaceutical, the clinical trial application of GFH925, a new class 1 drug, was accepted
.

It is reported that the target of GFH925 is KRAS G12C, which is intended to be developed for the treatment of solid tumors such as NSCLC.

RAS is the first oncogene identified in human tumors, and it is also one of the most widespread oncogenic mutation genes
.

The RAS gene family includes KRAS, NRAS and HRAS.

KRAS gene mutations are mainly concentrated in the positions of codons 12, 13 and 61, of which the mutations in the position of codon 12 account for more than 80%, including G12A, G12C, G12D, G12R, G12S and G12V
.

KRAS G12C mutations account for 12% of all KRAS mutations and have different incidences in different cancers.
Among them, it accounts for about 13% in NSCLC, about 3%-5% in colorectal cancer, and in other solid tumors.
About 1%-2%
.

Moreover, the incidence of KRAS G12C mutations in Asian and non-Asian populations is also different

At present, no KRAS G12C targeted drug has been approved in the world, but many drugs are in clinical trials
.

Among them, Amgen’s sotorasib (AMG 510) has made the fastest progress.

Research KRAS G12C inhibitor                        (incomplete statistics)

       Sotorasib is the first small molecule KRASG12C inhibitor that has successfully targeted KRAS and entered human clinical development.
It specifically and irreversibly inhibits its pro-proliferation activity by locking the G12C mutant KRAS protein in a non-activated GDP binding state
.

The Phase II study CodeBreaK 100 data on which its marketing application is based shows that sotorasib exhibits long-lasting anti-tumor activity in advanced NSCLC patients with KRAS G12C mutation who have previously received chemotherapy and/or PD-1/PD-L1 immunotherapy.

       Adagrasib (MRTX849) was developed by Mirati Therapeutics.
Through irreversible binding with the inactive KRAS G12C mutant, it "locks" them in the inactive conformation, thereby inhibiting KRAS-mediated signaling pathways.
It is currently in Phase III clinical trials.
Research phase
.

In July 2019, Mirati Therapeutics and Novartis reached a clinical collaboration to evaluate the combination therapy of MRTX849 and TNO155 (a SHP2 inhibitor) in the treatment of patients with advanced solid tumors with KRAS G12C mutations

       LY3537982 is a new generation of KRAS G12C inhibitor developed by Eli Lilly.
The preclinical research data announced at the AACR annual meeting held in April this year showed that the target binding rate of LY3537982 is greater than 90%, which is much higher than the 45-70% of AMG510.
, 60% of MRTX849
.

Moreover, the drug showed high target inhibitory activity in the KRAS-G12C mutant H358 lung cancer cell line, with IC50 (half inhibitory concentration

       ARS-3248 is a new generation of KRAS G12C inhibitor developed by Araxes (a subsidiary of Wellspring) based on ARS-1620.
In July 2019, Wellspring and Janssen collaborated to bring the drug to clinical trials
.

Araxes (a subsidiary of Wellspring) is one of the first companies to get involved in the new mutation site of KRAS.

       BPI-421286 is a new type of potent and highly selective covalent irreversible KRAS G12C oral small molecule inhibitor developed by Betta Pharmaceuticals.
It is intended to be used for unresectable, locally advanced or metastatic KRAS G12C-specific oncogene mutations.
The treatment of patients with solid tumors was approved for clinical use in China in April this year
.

       D-1553 is a KRAS G12C inhibitor independently developed by Yifang Bio.
It is used to treat cancers such as non-small cell lung cancer and colorectal cancer with KRAS G12C mutations.
It has been launched in the United States, Australia, China and other countries and regions.
The international multi-center phase I/II clinical trial
.
Pre-clinical studies have shown that: D-1553 has excellent selectivity and tumor suppressor effect.
Compared with similar drugs under investigation, it has higher bioavailability and low plasma protein binding rate
.

       JAB-21822 is a small molecule KRAS G12C inhibitor independently developed by Jacos Pharmaceuticals.
In internal head-to-head research, it has stronger oral bioavailability and systemic drug exposure than similar drugs, and has better pharmacokinetics.
Kinetic characteristics and tolerance
.
In May of this year, the drug was approved for clinical use in the United States
.

       GH35 is the first clinical trial application submitted by Qinhao Pharmaceutical in China
.
Preclinical studies have shown that: GH35 has high selectivity, good metabolism and safety
.
In April this year, the clinical trial application of GH35 was accepted by CDE
.

       Since the discovery of the RAS gene in 1982, from what was initially thought to be unpreparable, to now the first drug was reported for production, and many drugs entered the clinical stage, scientists and companies have made too many unknown efforts and look forward to the first KRAS G12C inhibitor.
Can be approved for listing as soon as possible
.

       However, acquired resistance to KRAS G12C inhibitors has emerged in clinical studies
.
At the 2021 AACR annual meeting, the Dana-Farber Cancer Institute reported that patients in clinical trials have progressed after treatment with Adagasib, and researchers have found that KRAS changes on multiple targets and off-target bypass mechanisms have led to the emergence of gains in patients Sexual resistance
.
In the future, the development of KRAS G12C inhibitors still has a long way to go, and scientists will continue to work tirelessly for it
.