KINTOR PHARMA-B (09939) Molecularly targeting c-Myc has published the results of the compound research in the Nature sub-journal.

On March 13th, KINTOR PHARMA-B (09939) announced that it had recently published a paper with its partners in the Nature sub-journal Nature Communications. The article mainly analyzed the mechanism by which MYC induces resistance to CDK4/6 inhibitors by promoting pRB1 degradation, and proposed that the c-Myc degrader A80.2HCl can enhance the therapeutic effect of CDK4/6 inhibitors. CDK4/6 regulates the progression of the early G1 phase of the cell cycle, which has a profound impact on the treatment of various solid tumors. CDK4/6 inhibitors have been approved for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, but their application in other tumors and their intrinsic resistance mechanisms are still unclear. In existing mechanistic studies, loss of normal RB1 function is considered a common reason for resistance to CDK4/6 inhibitors. MYC is one of the most widely studied oncogenic proteins, which can regulate many cellular processes and promote tumor development in various types of cancers, leading to therapy resistance. A80.2HCl is a molecular gel compound independently developed by KINTOR PHARMA, which can degrade c-Myc/GSPT1 and shows nanomolar level anti-tumor activity in various cancer cells such as bladder cancer/prostate cancer/breast cancer. In breast cancer and bladder xenograft models, A80.2HCl when used alone or in combination with the CDK4/6 inhibitor palbociclib, demonstrates good anti-tumor activity. Additionally, A80.2HCl has been shown to overcome palbociclib-induced drug resistance and enhance its drug sensitivity. The study found that: - High expression of MYC may cause loss of pRB1 function, leading to resistance to CDK4/6 inhibitors; - High expression of MYC mainly reduces the protein level of pRB1 through the proteolytic pathway; - E3 ubiquitin ligase KLHL42 interacts with pRB1, inducing pRB1 protein degradation; - As a target of MYC transcription factor, KLHL42 can mediate resistance to CDK4/6 inhibitors; - A80.2HCl is a molecular gel compound that degrades MYC; - A80.2HCl can enhance the therapeutic effect of CDK4/6 inhibitors. The researchers concluded that high expression of MYC may induce resistance to CDK4/6 inhibitors by directly activating the transcription of the E3 ubiquitin ligase KLHL42, promoting ubiquitination and degradation of pRB1, leading to a lack of pRB1 protein. The MYC inhibitor A80.2HCl developed by KINTOR PHARMA can degrade MYC at the nanomolar level, restore the activity of pRB1 protein, and alleviate resistance to CDK4/6 inhibitors associated with high MYC expression. In addition, the combination of CDK4/6 inhibitors and A80.2HCl showed synergistic cytotoxic effects on tumor cells in in vitro and in vivo studies.