c-Myc Degrader Study Published in Subsidiary Journal of Nature
Suzhou, 13 March, 2024 - Kintor Pharmaceutical Limited (“Kintor Pharma”, HKEX: 9939.HK), a clinical-stage biotechnology company developing innovative small molecule and biological therapeutics, announces that Kintor and its cooperative partner had published an article named MYC Induces CDK4/6 Inhibitors Resistance by Promoting pRB1 Degradation in a subsidiary journal of Nature—Nature Communications (Impact factor: 16.6). Nature Communications is one of the top journals in biology field and is classified as Q1 in several categories, representing a leading research level in the world. The study shows that target c-Myc molecular glue compound has great potential, which could provide more directions for overcoming resistance issues of CDK4/6 inhibitors in various tumor fields.
Issue
This article analyzes the mechanism of c-Myc that induces CDK4/6 inhibitors resistance and introduces A80.2HCl, a promising molecular glue compound developed by Kintor Pharma, to enhance the therapeutic efficacy of CDK4/6 inhibitors.
Background
CDK4 and CDK6 (CDK4/6) govern progression through the early G1 phases of the cell cycle, and they have shown profound effects against several solid tumors. CDK4/6 inhibitors (CDK4/6i) have been approved for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. However, their application to other tumor types and intrinsic resistance mechanisms are still unclear. Existing mechanism studies have shown that the loss of normal RB1 function is the most frequently observed change in cells resistant to CDK4/6i. MYC is one of the most widely investigated oncoproteins that regulates many cellular processes and contributes to tumorigenesis and therapeutic resistance in several different cancer types. This article analyzes the mechanism of MYC that induces CDK4/6 inhibitors resistance by promoting pRB1 degradation and introduces a c-Myc degrader A80.2HCl, a promising molecular glue compound developed by Kintor Pharma, to enhance the therapeutic effectiveness of CDK4/6 inhibitors.
Results
High MYC expression drives resistance to CDK4/6i by masking pRB1
High MYC expression reduces pRB1 abundance via proteasomal degradation
The E3 ubiquitin ligase KLHL42 interacts with pRB1 and induces pRB1 proteasomal degradation
KLHL42 is a transcriptional target of MYC that mediates CDK4/6i resistance
Identification of A80.2HCl as a MYC-degrading molecule
A80.2HCl potentiates the therapeutic efficacy of CDK4/6 inhibitors
Conc
lus
ion
High MYC expression drives resistance to CDK4/6i by directly activating the transcription of the E3 ubiquitin ligase KLHL42, which promotes pRB1 ubiquitination and degradation and thus leads to pRB1 protein deficiency
A molecule that degrades MYC, A80.2HCl, developed by Kintor Pharma, to abolish MYC when applied at nanomolar levels, rescues pRB1 protein activity, and diminishes MYC-dependent CDK4/6i resistance
The combination of CDK4/6i and MYC-degrading molecule A80.2HCl shows an additive effect on killing tumor cells both in vitro and in vivo
Full article：
The full article is available in Nature Communications.
Download: https://www.nature.com/articles/s41467-024-45796-w
About A80.2HCl
A80.2HCl, developed by Kintor Pharma, is a molecular glue drug with potent c-Myc/GSPT1 degradation and anti-tumor cell activity in nanomolar rages in a variety of cancer cell lines including bladder, prostate and breast cancer. A80.2HCl has been demonstrated potent anti-tumor activity as a single agent or combo with palbociclib in breast cancer and bladder xenograft tumor models. Moreover, A80.2HCl has been revealed to overcome palbociclib induced drug resistance and improved the drug sensitivity.
About Kintor Pharmaceutical Limited
Kintor Pharmaceutical Limited is developing and commercializing a robust pipeline of innovative small molecule and biological therapeutics for oncology and androgen-receptor-related disease areas with unmet medical needs, including alopecia, acne, COVID-19, prostate cancer, liver and breast cancers. For more information, visit www.kintor.com.cn.
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