PROTAC is the world's first innovative drug for the treatment of NASH
Nonalcoholic steatohepatitis (NASH) Nonalcoholic steatohepatitis (NASH) is an important part of the progression of liver cirrhosis, hepatocellular carcinoma, liver failure and other end-stage liver disease, and the probability of cirrhosis in Nash patients within 10-15 years is as high as 15%-25%. NASH is expected to affect 490 million people in 2030. EvalutePharma estimates that the NASH drug market has reached $40 billion, and the market value is huge. However, the complexity of NASH pathology makes it difficult to develop new drugs. At present, there is no FDA-approved NASH treatment drug on the market, and all NASH drug candidates entering phase 3 clinical trials by internationally renowned pharmaceutical companies such as Gilead, Novartis and Genfit have failed, especially Gilead has failed phase 2 and phase 3 clinical trials in a number of NASH mechanisms. Therefore, to develop effective drugs for NASH, it is necessary to crack the pathogenesis of NASH, discover new therapeutic targets for NASH, and use novel technologies to develop a new generation of innovative drugs for NASH treatment.
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Project profile
01.Project profile
Based on iRhom2, a new therapeutic target for NASH discovered by a certain company, and a new strategy of ubiquitination degradation of iRhom2 targeted by Trim31 to treat NASH, protein degradation targeting chimera technology was adopted. We designed, synthesized and screened PROTAC, a bi-functional molecule that can link E3 ligase Trim31 and inflammation related protein iRhom2, which has the function of targeting iRhom2 degradation and significantly reducing insulin resistance, hepatic steatosis and inflammatory phenotype. PROTAC is the world's first protein degradation targeting chimera for the treatment of NASH.
02.Technical introduction
(1) Innovation achievements. We found a new target for the treatment of NASH - iRhom2 and its new mechanism of degradation by ubiquitination. Published in Nature Communications and Hepatology in 2021 and 2022, respectively. It is the first time in the world to propose iRhom2 protein degradation targeting chimera (PROTAC) for the treatment of NASH.
03.Project phase
The project is in the pre-clinical study, the candidate drug molecules have been obtained, and the pharmacodynamic experiments have been completed.
04.Key personnel
Director of a key laboratory
He graduated from Chongqing University and is a postdoctoral researcher at the California Institute of Technology. Chongqing Talent Program • Innovation and entrepreneurship leading talents, has undertaken the National Natural Science Foundation, "Twelfth Five-Year" national major new drug creation special. He has published more than 100 papers, 14 authorized invention patents, and 3 provincial and ministerial science and technology awards.
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Market competitive advantage
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Overcoming drug resistance
Different from the mechanism of stimulating or inhibiting the target protein of traditional drugs, PROTAC directly catalyzes the degradation of the target protein and reduces the abundance of the target protein, which makes PROTACs drugs have the advantage of no drug resistance.
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Improve targeting selectivity and reduce toxicity
PROTAC requires simultaneous binding of target protein and E3 ligase to allow target protein degradation, which can avoid unexpected side effects. Thus, selectivity and targeting are high, and toxicity is reduced.
03
Reduce kinase-independent dependence
iRhom2 is kinase independent and simple inhibition is very effective. The use of PROTAC can solve problems that are not easy to solve with traditional small molecule inhibitors.
04
Reduce the target of "unready medicine"
The surface of iRhom2, an "unpharmaceutical" target protein, is flat and smooth, and it is difficult to find effective binding sites for small molecules. Therefore, PROTAC technology provides the feasibility of efficient and selective degradation of iRhom2.
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Financing demand
Equity financing of 15 million, 10-15% of the shares sold, used to carry out PROTAC synthesis process, pharmacology, safety evaluation, preparation and other preclinical research, IND declaration. It mainly raises external funds, such as applying for the government's special fund for innovative drug research, the government's pioneer industry fund, and the pharmaceutical investment fund.
