SUZHOU, China and ROCKVILLE, Md., Nov. 29, 2020 /PRNewswire/ -- Ascentage Pharma (6855.HK), a globally focused, clinical-stage biotechnology company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, today announced it has entered into an agreement with the University of Michigan, through which the company may obtain the exclusive global rights to a MDM2 protein degrader developed using the Proteolysis-Targeting Chimeras (PROTACs) technology. The drug candidate is currently entering IND-enabling studies.
MDM2 is a key regulator of the tumor suppressor p53 and one of the most potent inhibitors of apoptosis discovered thus far. It has high expression in tumors and plays a key role in the occurrence and development of tumors. Binding to the MDM2 protein with high affinity, MDM2 inhibitor blocks the MDM2-p53 interactions and restore the tumor-suppressing activity of p53.1 Meanwhile, these MDM2 inhibitors present some challenges, including dose-limiting hematological toxicities, thus the urgent need to develop new generation of MDM2-targeting therapies in the treatment of cancer. The PROTAC technology has emerged as a new and promising approach that induces the degradation of targeted proteins through the ubiquitin-proteasome system (UPS), and it has received widespread interest from both the scientific community and industries since its introduction. Compared to conventional "occupancy-driven" pharmacological modality, the "event-driven" PROTAC technology has many advantages, such as high potency, high selectivity, with catalytic mode of action, and the ability to target undruggable proteins.2
Prof. Shaomeng Wang, Ph.D., Co-Founder of Ascentage Pharma and Chairman of its Scientific Advisory Board, and Warner-Lambert/Parke-Davis Professor in Medicine, Professor of Internal Medicine, Pharmacology and Medicinal Chemistry, Director of Michigan Center for Therapeutic Innovation, University of Michigan, is a leading researcher in the field. Through structure-function studies of their previously discovered MDM2 inhibitors using the PROTAC technology, Dr. Wang's research team has obtained potent and efficacious MDM2 degraders that could effectively induce rapid degradation of MDM2. The lead MDM2 degrader has achieved complete and durable tumor regression in a xenograft tumor model in mice3.
"As a new strategy to induce protein degradation, PROTAC has emerged as a novel modality in drug discovery," said Dr. Wang. "Studies showed, PROTAC-induced MDM2 degradation can not only enhance the potency of MDM2 inhibitors, but also maintain a long-lasting suppression of MDM2 protein levels, providing a new strategy to the treatment of MDM2-driven tumors such as leukemia. We look forward to the further development of the asset by Ascentage Pharma."
"The emergence of the PROTAC technology represents another breakthrough in the identification of small molecule drugs. The technology has received tremendous interest for its ability to target undruggable proteins," said Dr. Dajun Yang, Chairman & CEO of Ascentage Pharma. "We are very pleased to reach this agreement with the University of Michigan, to begin the assessment of this PROTAC-based MDM2 degrader and potentially bring this important addition to our existing pipeline. Through the assessment and potential development of the MDM2 degrader, we hope soon that it will offer an effective therapy for serious unmet medical needs."
Zhao, Y.; Aguilar, A.; Bernard, D.; Wang, S. Small-molecule inhibitors of the MDM2-p53 protein-protein interaction (MDM2 inhibitors) in clinical trials for cancer treatment. J. Med. Chem. 2015, 58, 1038−1052.
Lai, A. C.; Crews, C. M. Induced protein degradation: an emerging drug discovery paradigm. Nat Rev. Drug Discov. 2017, 16, 101-114.
Ryan P. Wurz and Victor J. Cee. Targeted Degradation of MDM2 as a New Approach to Improve the Efficacy of MDM2-p53 Inhibitors. J. Med. Chem. 2019, 62, 445−447.
About Ascentage Pharma
Ascentage Pharma (6855.HK) is a globally, clinical-stage biotechnology company engaged in developing novel therapies for cancers, CHB, and age-related diseases. On October 28, 2019, Ascentage Pharma was listed on the Main Board of the Stock Exchange of Hong Kong Limited with the stock code: 6855.HK.
Ascentage Pharma focuses on developing therapeutics that inhibit protein-protein interactions to restore apoptosis or programmed cell death. The company has built a pipeline of eight clinical drug candidates, including novel, highly potent Bcl-2, and dual Bcl-2/Bcl-xL inhibitors, as well as candidates aimed at IAP and MDM2-p53 pathways, and next-generation tyrosine kinase inhibitors. Ascentage Pharma is also the only company in the world with active clinical programs targeting all three known classes of key apoptosis regulators. The company is conducting more than 40 Phase I/II clinical trials in the US, Australia, and China. HQP1351, the company's core drug candidate developed for the treatment of drug-resistant chronic myeloid leukemia has been granted an Orphan Drug Designation (ODD) and a Fast Track designation by the US Food and Drug Administration (FDA), and a New Drug Application for the drug candidate has been submitted in China. To date, Ascentage Pharma has obtained a total of six ODDs from the FDA for four of the company's investigational drug candidates.
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