Originals . . . Nimbus Parade

Today Nimbus, an American biopharmaceutical company, announced six projects in its research lineIn addition to tyk2 and HPK1, four new projects, AMPKb2, CTPS1, Cbl-b, and WRN, were announced today, but the termination of STING was announcedNimbus has received $1.2 billion in high-intensity funding in its years of existence, and cooperation with big pharmaceutical companies has also been notable, such as the sale of ACC2 inhibitor NDI-010976 (later renamed GS-0976) to Gilead in 2016 and the development of small molecule checkpoint HPK1 inhibitors last year with New BaseCEOs say the industry often praises them for looking for interesting targets, and they're proud of itdrug source analysisbiotech companies do not often fully disclose their products in research to avoid exposure to the main forceNimbus such a high-profile military parade is not common, is also estimated to be trying to build a bold imageTo say that these targets are interesting should be opposed by no one, these are key regulatory proteins supported by stronger genetic dataBut these targets are also small molecular drug projects with higher drug chemistry difficulties, many are relatively old targets, but because of the lack of target structure information and suitable small molecular skeletons so that there has been no progress for many yearsNimbus says doing some basic research first to make strategic reserves for besieging these targetsthese targets, Tyk2 is relatively mature, Shi Guibao has a product in Phase III clinical, its second clinical data is quite goodTyk2 is the Jak family protein that plays a key role in certain autoimmune diseases such as psoriasisAlthough Jak inhibitors are already available, the development of kinase inhibitors outside of tumors is difficult, mainly because kinase inhibitors pull radish out of the mud and are difficult to be very cleanMost kinases are associated with cell division and growth, so off-target activity often brings more serious side effectsTyk2 has a positive point because the enzyme has a pseudokinase regulatory mechanism, and this pseudokinase is far different from other kinase structures, so give sphenosis to increase selectivityAnother kinase HPK1 is one of the earliest small molecule checkpoints, only after The T cell is activated, and basically in the immune cell expression, so in theory is a highly selective targetBut this kinase is very close to many other kinase structures, so if the compound has off-target activity to interfere with other kinases there is still a selective problem Inhibition of HPK1 can further activate T cells and accelerate T-cell growth, but if off-target activity inhibits the division of T cells will be lost Off-target activity is not important to lethal kinase inhibitors, but is essential for active compounds both ampK and ACLY are older metabolic targets , but there has been little progress due to the lack of suitable molecular skeletons AMPK is also a kinase, activated to speed up fat metabolism, lower blood sugar, the effect is like physical exercise, so very lazy people yearn for But this requires the drug to activate rather than suppress the protein Selective inhibition of kinases is difficult, selective activation is more difficult, Nimbus prepares selective binding b2 units, and may be cleaner ACLY IS A KEY REGULATORY PROTEIN FOR CHOLESTEROL METABOLISM, BUT BECAUSE THE SUBSTRATE IS A VERY POLAR CITRIC ACID, COMPETITIVE INHIBITORS ARE NOT AS A DRUG." Esperion's simple small molecule drug, bempedoic acid, has been claimed to activate AMPK at the same time and inhibit ALCY, but has recently appeared to have abandoned the term AMPK activity WRN caused quite a stir by publishing two Nature articles in the same week last year Unlike the chemotherapy era, which flaunts broad-spectrum anti-cancer activity, WRN emphasizes the high selectivity of synthetic death with MSI Similar to PARP, only some tumors with specific genetic markers rely on WRN, which may expand the treatment window WRN is a DNA de-cyclone that is so different from traditional targets that a new structure type needs to be found first to find high-quality precursors CLB-b is a member of the Revlimid Target family of today's small molecule drug king, and is an E3 link enzyme Such targets are also poorly medicinal because they work through protein interactions Now more than 600 E3 has only a few more active and higher ligands Hudlicky complained last week about the decline of organic chemistry, it is clear that conquering these targets also requires deep involvement in organic chemistry Nimbus, which started out as a technical platform for structural inhibitors, is now said to have increased its ability to design molecule-based drug While these are growing technology platforms that seem a bit difficult to integrate directly into the sharp-knife platoon, they are created to solve the industry's core challenge of not being a drug-making target Some people often lament that the low-hanging fruit has been picked, but in fact which fruit was not the low-hanging fruit until it was picked The reason why it is now low-hanging fruit is that someone like Nimbus is now hit by mountains, water bridges, these warriors are the driving force behind the pharmaceutical industry's progress.