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 ful...
(All Rights Reserved)