On November 29, 2020 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, reported 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 (Press release, Ascentage Pharma, NOV 29, 2020, View Source [SID1234571915]). The drug candidate is currently entering IND-enabling studies.

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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., C-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."

References:

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.