The first phase of the cooperation project between Baiji Shenzhou and Merck xuelanuo for PARP inhibitors was successful

The latter paid $9 million in milestone payments to Baekje under the agreement This is Merck's second milestone payment since the cooperation with Baiji Shenzhou, and the first payment disclosed by PARP inhibitor cooperation project The two sides signed a cooperative development agreement on PARP inhibitors in November last year, but did not disclose the amount of advance payment Poly adenosine diphosphate ribose polymerase (PARP) is a kind of cellular ribozyme which plays a key role in eukaryotic cells When affected by radiation, oxidation or chemotherapy drugs, the double or single strand structure of DNA is often damaged PARP-1 can be detected rapidly through its zinc finger structure and bind with the gap of DNA damage, leading to the activation of PARP, catalyzing the ADP ribose polymerization with β - NAD + as the substrate, synthesizing polyadenyldiphosphate ribose (PAR), and causing chromosome relaxation, promoting the migration and binding of repair factors such as DNA repair enzyme, XRCC1 and DNA ligase III to DNA damage site, completing the repair of damaged DNA 。 Parp-1-mediated DNA repair, on the one hand, is essential to maintain the integrity of human genome, on the other hand, is one of the important factors leading to chemotherapy or radiotherapy resistance In addition, according to the theory of synthetic lethality, if there is a synthetic lethality between two genes, when any one of them is inhibited or mutated alone, the survival of cells will not be affected, but inhibition of both genes will lead to apoptosis In this way, PARP inhibitors are not only sensitizers for chemotherapy and radiotherapy, but also can inhibit tumors including BRCA-1 / 2 gene mutations or HR defects when used alone Although PARP is a very effective molecular target in theory, the development of PARP inhibitors is not smooth Drug sources have also repeatedly introduced the legend and twists and turns of the development of PARP inhibitors All in all, by 2013, the clinical development of PARP inhibitors will be improved, at least including olaparib of AstraZeneca, veliparib of Alberta, bmn-673 of biomarin, rucaparib of Clovis oncology, and niraparib of tesaro On June 25 this year, the FDA's anti-tumor drug advisory group (ODAC) voted 11:2 to not recommend olaparib, a PARP inhibitor of AstraZeneca, as a single drug for women with BRCA gene mutation, who are sensitive to platinum chemicals but have relapsed advanced ovarian cancer Although the voting results mainly question the clinical experimental design of olaparib, and require AstraZeneca to continue to complete the confirmatory phase III clinical (Solo-2), it still has a certain negative impact on the "resurgence" of PARP inhibitor research field The development of PARP inhibitor is one of the first projects in Baiji since its establishment in 2011 Although the chemical structure of bgb-290 has not been reported yet, two PARP inhibitor patents of Baiji Shenzhou have been applied in December 2011, which is less than two years different from bmn-673 of lead therapeutics purchased by biomarin in February 2010 with us $18 million Bmn-673 of the latter claims to be the most active known PARP inhibitor Although the research of PARP inhibitors was at a low ebb at that time, we can see the shadow of bmn-673 from the general formula of Parkson's PARP inhibitor patent (see the general formula of the two patents below), which is one of the by-products of structural transformation of AstraZeneca olaparib For example, the development of Baiji Shenzhou bgb-290 is "just in time" When the pre clinical work was completed in 2013, it coincided with the rapid progress of PARP inhibitors Merck xuelanuo subsequently signed a contract with it To be sure, the research and development of bgb-290 is a great success for Baiji Shenzhou The research work in less than one year directly leads to at least 9 million US dollars Moreover, if the clinical development and commercialization are successful in the future, Baiji can get as much as 170 million euros On the contrary, Merck's cooperation with baiji is puzzling PARP is a very old molecular target It has been developed in cardiovascular disease since the 1990s As an anti-tumor target drug, PARP has been developed as early as 10 years ago The first PARP inhibitor would have been in the drugstore if it hadn't been blocked And Merck's mk-4827 was later transferred to tesaro (renamed niraparib) Although Merck xuelanuo and Merck are relatively independent, in today's high-quality / high drug price payment environment, most of the pharmaceutical giants have left me too product development one after another Merck xuelanuo even went against the wind, which is confusing after all Of course, the "one step, three shakes" in the development of PARP inhibitors is conducive to the catch-up of Baiji Shenzhou / Merck xuelanuo, but other research lines in Baiji Shenzhou, such as BRAF, Btk, and PD-1 inhibitors, have already had similar products on the market, so it is difficult to win an important sales share in the western pharmaceutical market (BIOON Com) general formula of the patent wo2013097225 / wo2013097226 of Parkson PARP inhibitor