Study of Kintor's C-Myc Degrader Published in Subsidiary Journal of Nature
Study of Kintor's C-Myc Degrader Published in Subsidiary Journal of Nature
SUZHOU, China, March 14, 2024 /PRNewswire/ -- 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.
中國蘇州，2024 年 3 月 14 日 /PRNewswire/ — Kintor Pharmaceutical Limited (”Kintor 製藥“，HKEX：9939.HK）是一家開發創新小分子和生物療法的臨床階段生物技術公司，宣佈Kintor及其合作伙伴發表了一篇名爲的文章 MYC 通過促進 prB1 誘導 CDK4/6 抑制劑耐藥性 附屬期刊中的降解 自然—自然通訊 （影響因子：16.6）。 自然通訊 是生物學領域的頂級期刊之一，在多個類別中被列爲第一季度，代表了世界領先的研究水平。研究表明，靶向c-MYC分子膠化合物具有巨大潛力，可以爲克服CDK4/6抑制劑在各個腫瘤領域的耐藥問題提供更多指導。
Issue:
問題：
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.
本文分析了c-MYC誘導CDK4/6抑制劑耐藥性的機制，並介紹了A80.2HCl，這是一種由Kintor Pharma開發的有前途的分子膠化合物，用於增強CDK4/6抑制劑的治療功效。
Background:
背景：
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.
CDK4和CDK6（CDK4/6）控制細胞週期早期G1階段的進展，它們對幾種實體瘤顯示出深遠的影響。CDK4/6抑制劑（CDK4/6i）已獲准用於治療激素受體（HR）陽性的人表皮生長因子受體2（HER2）陰性的晚期或轉移性乳腺癌。但是，它們對其他腫瘤類型和內在耐藥機制的應用仍不清楚。現有機制研究表明，正常RB1功能的喪失是對CDK4/6i具有抗性的細胞中最常觀察到的變化。MYC 是研究最廣泛的癌蛋白之一，它調節許多細胞過程，並促進幾種不同癌症類型的腫瘤發生和耐藥性。本文分析了MYC通過促進prB1降解誘導CDK4/6抑制劑耐藥性的機制，並介紹了一種c-MYC降解劑A80.2HCl，這是一種前景廣闊的分子膠化合物，以增強CDK4/6抑制劑的治療效果。
Results:
結果：
- 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
- 高 MYC 表達通過屏蔽 prB1 來增強對 cdk4/6i 的抵抗力
- 高 MYC 表達通過蛋白酶體降解降低 prB1 丰度
- E3 泛素連接酶 KLHL42 與 prB1 相互作用並誘導 prB1 蛋白酶體降解
- KLHL42 是介導 CDK4/6i 耐藥性的 MYC 轉錄靶標
- 鑑定 A80.2HCl 爲 myc 降解分子
- a80.2HCl 可增強 CDK4/6 抑制劑的治療功效
Conclusion:
結論：
- 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
- 高 MYC 表達通過直接激活 E3 泛素連接酶 KLHL42 的轉錄來驅動對 CDK4/6i 的耐藥性，後者促進 prB1 泛素化和降解，從而導致 prB1 蛋白缺乏
- A80.2HCl 是一種降解 MYC 的分子，由 Kintor Pharma 開發，在應用於納摩爾水平時可消除 MYC，恢復 prB1 蛋白活性，並降低依賴性 MYC 的 CDK4/6i 耐藥性
- CDK4/6i 和 myc 降解分子 A80.2HCl 的組合顯示出對體外和體內殺死腫瘤細胞的增效作用
Full article:
完整文章:
The full article is available in Nature Communications.
Download:
完整文章可在 自然通訊。
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SOURCE Kintor Pharmaceutical Limited
來源 Kintor 製藥有限公司
譯文內容由第三人軟體翻譯。