Beijing, Shanghai, Boston, August 12, 2024-Jacobio Pharma (1167.HK), a clinical-stage oncology company focusing on undruggable targets, today announced that the preclinical research results of its in-house developed SHP2 inhibitor JAB-3312 were published in prestigious journal, the Journal of Medicinal Chemistry. In the article, Jacobio disclosed the structure of JAB-3312 for the first time, highlighted that the binding pocket of JAB-3312 is significantly different from other SHP2 inhibitors, and defined a new allosteric site of SHP2.

In this article, Jacobio's pre-clinical team detailed the key ideas and experimental results in the molecular design process. After confirming the extra-pockets that can be used in the new allosteric site, the research team constructed a new molecular mother ring. In the co-crystal analysis of the newly designed molecules and SHP2 protein, it was found that the newly designed molecules can better bind to the newly discovered allosteric sites, enhancing the binding and inhibitory activity of such molecules on SHP2. While focusing on the ability to inhibit SHP2, the research team iteratively optimized other pharmacokinetic parameters of the molecule, and finally optimized the highly efficient SHP2 inhibitor JAB-3312 with balanced parameters.

JAB-3312 showed higher affinity for the SHP2 allosteric site and stronger SHP2 phosphatase inhibitory activity. JAB-3312 was over than 20 times more potent than other SHP2 inhibitors in the preclinical setting, which translated into the lowest clinical dose (1-4 mg QD) amongst all SHP2 inhibitor to be used in clinical trials. 

"There are about 180 disease-related protein phosphatases in the human body, but none of them have been successfully developed into drugs, so protein phosphatases are labeled as ‘difficult-to-drug’ targets. JAB-3312 is the only protein phosphatase inhibitor globally that has entered a phase III registration clinical trial, and it is also the only second-generation SHP2 inhibitor. The breakthrough of SHP2 has not only provided tremendous clinical value, but also carried out scientific significance, providing an important milestone for the development of more protein phosphatase inhibitors in the future. We hope that through the publication of this article along with promising clinical data from our ongoing KRAS G12C inhibitor plus SHP2 inhibitor trial, we can bring confidence to all SHP2 inhibitor developers and protein phosphatase researchers," said Dr. Yinxiang Wang, Chairman and CEO of Jacobio.

Jacobio has initiated the clinical development SHP2 inhibitors since 2018, and the clinical results from SHP2 trials reported at major international oncology conferences have generated considerable excitement in the field. According to data presented at the American Society of Clinical Oncology (ASCO) Annual Meeting in June 2024, glecirasib in combination with JAB-3312 resulted confirmed objective response rate (cORR) of 64.7% (66/102) and preliminary median progression-free survival (mPFS) of 12.2 months in the front-line NSCLC. The optimal dosing schedule glecirasib at 800 mg daily combined with JAB-3312 at 2 mg daily one week on and one week off resulted a cORR of 77.4% (24/31), and 54.8% (17/31) of patients achieved a deep response with tumors shrinking by more than 50%. Regarding on the safety data from all study patients the incidence of grade 3 or 4 treatment-related adverse events (TRAE) was 43.8%, and there was no treatment-related death. The overall safety is manageable.

About JAB-3312
JAB-3312 is a highly selective SHP2 inhibitor with best-in-class potential. JAB-3312 is currently conducting multiple clinical trials in China and the United States, including the combination therapy trial with KRAS G12C inhibitor glecirasib. JAB-3312 is the only SHP2 inhibitor in the world to enter Phase III trials, and Phase III clinical trials are underway in combination with glecirasib for the first-line treatment of KRAS G12C mutations.
 

About Jacobio