Shortly before the wen/drug madness, No cheng Jianhua released the 2020 interim results report, introduced the company's important varieties of progress and part of the research projects, of which SHP2 target inhibitors are particularly eye-catching.
SHP2 is a powerful oral variant inhibitor, codened ICP-189, and the adaptation is intended for the treatment of solid tumors and can be used as a combination therapy for monotherapy and/or in combination with other anti-tumor drugs, with an IND application scheduled to be submitted to NMPA in the second half of 2021.
the above information is not difficult to push back, SHP2 inhibitor this variety of preclinical pharmacology, pharmacological substitute, toxicology generation and other trials should have completed most of the content.
, what are the characteristics of SHP2 as a target, path and its inhibitors? Why would an innovative company choose this target? Figure 1.1 Noshing Jianhua Pharmaceutical Research and Development Pipeline (Photo Source: Yu Jianhua Co., Ltd. - Mid-Six Months Ended June 30, 2020 Announcement) 1. SHP2 target structure characteristics through literature inquiries, protein tyrosine phosphatase (PTP) catalytic tyrosine dephosphate, is a key control element in mammalian signaling, the deviation of its biological function will cause the body regulation disorders leading to cancer, diabetes, autoimmune diseases and other diseases.
, Src isotopic 2 domain protein tyrosine phosphatase (SHP2) is currently the only confirmed primary cancer protein in the PTP family.
2.1 SHP2 structure and activation process (Photo: Acta Pharmaceutica Sinica B) 2. SHP2 signal path characteristics SHP2 is considered to be an ideal target for cancer intervention, mainly manifested in three aspects: First, SHP2 is a common node of multiple active RAS signaling path, activating RAS on the growth and survival of cancer cells Almost all RTKs activate SHP2 to activate the RAS signaling path, so a suitable SHP2 inhibitor can "net out" different RTK gene mutations, potentially becoming a broad-spectrum cancer drug.
3.1 SHP2 targets play a variety of roles in tumor processes (Photo: Pharmacological Research. 2019) Second, SHP2 inhibitors can be used in combination with kinase inhibitors due to the overlap of the protein tyrosine kinase (PTK) and the SHP2 signaling path path. The interconnected signal path is double-inhibited, and this combination therapy is more effective than a single therapy, which is neither susceptible to drug resistance nor reverses the obtainability resistance of PPK inhibitors, and finally, SHP2 participates in the signaling path of PD-1/PD-L1 at the program cell death checkpoint to regulate the activity of T cells.
signal path of SHP2 regulation in T-cells (Photo: Pharmacological Research. 2019) 3. SHP2 inhibitor development statistics at present, the global SHP2 inhibitors have not yet been listed, into the clinical stage of the development of very few varieties.
addition to the ICP-189 disclosed by Novartis, the clinical phase of the SHP2 inhibitors and Thevolution Medicines/Sanofi jointly developed the RMC-4630 (I// Phase II), RELY-1971 (Phase I) developed by Relay Therapeutics, and JAB-3068 (IIa) and JAB-3312 (Phase I) developed by Beijing Garcos, a domestic pharmaceutical company.
is highlighted here under the same domestic pharmaceutical company Garcos two SHP2 inhibitor products.
JAB-3068 is the first independently developed original innovative drug SHP2 inhibitor developed by Beijing Garcos, which has been approved for phase IIa clinical studies of multiple solid tumors and has been identified by the FDA as an orphan drug for esophageal cancer treatment.
, clinical trials conducted in China, single drug for esophageal squamous cancer / head and neck squamous cancer / non-small cell lung cancer has entered Phase II, with PD-1 antibody in a declared clinical state.
Another variety, JAB-3312, an oral anti-tumor drug designed and developed for Garcos with global intellectual property rights, has been clinically licensed by the FDA and China's NMPA, and clinical trials of single-drug solid tumors have entered Phase I.
Figure 4.1 Beijing Garcos SHP2 Clinical Phase Project (Photo:) 4. In summary, it is not difficult to see that SHP2 is a very new target in the field of oncology, and the global development of its inhibitors is also very small.
From the target point of view, it is related to the important signaling path, the possibility of the drug is still very large, and for the development of inhibitors, the domestic Garcos is more leading, and there are two drugs in the clinical, overall forward.
look back at No cheng Jianhua's variety pipeline, its innovative quality is very high, layout ideas are very clear, the old target to do very little, the future expectations are very high.
Source: 1. Research progress on the protein tyrosine phosphatase SHP2 and its inhibitors in the six months ended June 30, 2020 Bulletin. Pharmaceutical advances 3. Pharmacological Research. 2019 Pharmaceutica Sinica B. of Pharmacological Sciences. Signalling. doi:10.1016/j.cellsig.2007.10.0027.Seminars in Cell and Developmental Biology. doi.org/10.1016/j.semcdb.2014.09.0138.Pharmaproject Date