Fierce Competition of R&D of KRAS G12C Inhibitors

Recently, the class 1 new drug "ZG19018 Tablets" of Suzhou Zelgen Biopharmaceuticals Co., Ltd. is approved for clinical use in China and the indications are: advanced malignant solid tumors with KRAS G12C mutation. 

ZG19018 is a KRAS G12C selective covalent inhibitor developed by Zelgen, which can bind to the allosteric binding pocket below the KRAS protein molecular switch II region and form covalent binding with nearby Cys12. It locks KRAS G12C in a non-activated state bound to GDP, selectively inhibits the activation of KRAS G12C and suppresses the activation of multiple downstream signaling pathways, thereby inhibiting the proliferation of tumor cells and exerting anti-tumor effects. 

Preclinical study shows that ZG19018 has significant pharmacodynamic effects of inhibiting KRAS G12C mutation tumor growth and cell proliferation, with long drug half-life, high oral bioavailability, and high drug concentration in tumor and brain tissues. 

RAS was the first oncogene identified in human history, and its gene mutations are associated with about 20% of tumors, of which KRAS gene mutations are the most common type of RAS gene mutations, accounting for about 85%. KRAS G12C is a type of KRAS gene mutation, accounting for about 12%. The incidence of KRAS G12C gene mutations varies among cancer types, with approximately 13% in NSCLC, 3%-5% in colorectal cancer, and 1%-2% in other solid tumors. 

At present, the world's first KRAS G12C inhibitor, Amgen's Lumakras (sotorasib), has been released. Lumakras was approved by FDA in May this year for the treatment of patients with non-small cell lung cancer (NSCLC), the tumors of which carry KRAS G12C mutation. In accordance with the company's financial report, the sales of Lumakras in the third quarter of the year hits 36 million US dollars. 

Furthermore, a number of KRAS G12C inhibitors are currently under development, as detailed in the table below. If you want to know more about medical products online, then Pharmasource, a vertical e-commerce online platform serving the pharmaceutical industry, would be your best choice.

JDQ443 is an oral selective KRAS G12C covalent inhibitor developed by Novartis, which can irreversibly lock KRAS G12C into an inactivated state and has demonstrated promising anti-cancer activity in preclinical studies. 

GFH925 is an efficient oral new molecular entity compound independently developed by Genfleet with complete intellectual property rights. By covalently and irreversibly modifying the cysteine residue of KRAS G12C protein mutant, it effectively inhibits GTP/GDP exchange mediated by this protein, thus down-regulating the activation level of KRAS protein. Preclinical selective test for cysteine also shows high selective inhibitory effect of GFH925 on this mutation site. In addition, GFH925 can inhibit the downstream signal transduction pathway after inhibiting KRAS protein and effectively induce apoptosis and cell cycle arrest of tumor cells, thus achieving anti-tumor effect. According to the preclinical experimental data, GFH925 has the potential best-in-class activity. It can effectively inhibit the growth of various tumor cell lines with KRAS G12C mutation, which can accelerate the clinical validation. Besides, other preclinical trials also show the potential of combination with other therapies. 

D-1553 is a KRAS G12C inhibitor developed by Inventisbio for the treatment of NSCLC, colorectal cancer and other cancers with KRAS G12C mutation. 

JAB-21822 is a KRAS G12C small molecule antitumor drug independently developed by Jacobio, which is currently in clinical trials in China and the United States. JAB-21822 has a better oral bioavailability, systemic drug exposure, and better pharmacokinetic characteristics and tolerance in the internal head-to-head study compared to its counterpart. Preclinical study shows that: The combination of JAB-21822 and cetuximab can enhance the anti-tumor activity of JAB-21822 inhibitor in a colorectal cancer tumor model, regressing the tumor and delaying tumor regrowth after drug discontinuation. 

BPI-421286 is a novel, new molecular entity compound with fully independent intellectual property rights under Betta Pharmaceuticals, which is a novel potent, highly selective, covalent and irreversible KRASG12C oral small molecule inhibitor. According to preclinical data, BPI-421286 can effectively inhibit the proliferation of tumor cells carrying KRAS G12C mutation, and has shown good anti-tumor effect on various transplanted tumor models carrying KRASG12C mutation. 

GH35 is a KRAS G12C inhibitor developed by Genhouse Bio. Preclinical studies show that: GH35 is highly selective and extremely biologically active against KRAS G12C mutations, with no significant effect on wild-type KRAS and safety-related targets and low off-target risk. Moreover, the drug has excellent metabolic properties, high oral bioavailability and good safety profile. 

YL-15293 is a small molecule inhibitor of KRAS developed by Yingli Pharmaceutical, which has the same mechanism of action as Sotorasib and works by covalently binding to the cysteine in KRAS G12C mutant protein to lock the KRAS G12C mutant in an inactivated state. 

Adagrasib (MRTX849) is an orally optimized inhibitor that specifically targets KRAS G12C mutants by irreversibly and selectively binding to KRAS G12C in an inactive state, preventing it from sending cell growth signals and causing cancer cell death.

The research data show that: adagrasib has demonstrated definitive and durable antitumor activity in non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and other solid tumors, with the ORR of 45% for adagrasib monotherapy in advanced NSCLC. 

In addition, according to incomplete statistics, global pharmaceutical companies have entered into at least three licensing deals around KRAS G12C inhibitors this year. In June, Zai Lab and Mirati Therapeutics reached a cooperation agreement to obtain the development and exclusive commercialization rights of Adagrasib in China. In September, Innovent and Genfleet announced that they have reached an exclusive global licensing agreement to obtain the development and commercialization rights of GFH925 in China (including mainland China, Hong Kong, S.A.R., China, Macau, S.A.R., China and Taiwan, China), as well as the option of global development and commercialization rights. In November, HUYA Bioscience International reached an exclusive license agreement with Shanghai Jiyu, a subsidiary of Jemincare Group, and obtained the right to develop, produce and commercialize KRAS inhibitor JMKX1899 of the latter outside China. 

About  the Author:    

Yi, a pharmacist pays attention to the research and development trends of new drugs at home and abroad, expects to improve himself in the continuous input and output, and grow together with medical we-media.