AML-147 C-MYC Targeting by Degradation: Novel Dual c-Myc/GSPT1 Degrader GT19715 Exerts Profound Cell Kill In Vitro and In Vivo in Acute Myeloid Leukemia and Lymphomas

髓系白血病 体内 癌症研究 体外 泛素连接酶 髓样 祖细胞 分子生物学 泛素 干细胞 生物 化学 细胞生物学 生物化学 生物技术 基因
作者
Yuki Nishida,Darah A Scruggs,Edward Ayoub,Tallie Patsilevas,Vivian Ruvolo,Po Yee Mak,Bing Z. Carter,Steffen Boettcher,Abhishek Maiti,Qianxiang Zhou,Zhaohui Yang,Honghua Yan,Liandong Ma,Michael Andreeff
出处
期刊:Clinical Lymphoma, Myeloma & Leukemia [Elsevier BV]
卷期号:22: S218-S218 被引量:6
标识
DOI:10.1016/s2152-2650(22)01230-7
摘要

The oncoprotein c-Myc governs epigenome and transcriptome and is deregulated in 70% of all human cancers. MYC is highly expressed in TP53 mutant or venetoclax (ven) resistant AML (Sallman, Blood 2021, Nishida, ASH 2021). However, targeting c-Myc or the MYC pathway has not been met with success. PROTACs or cerebron E3 ligase modulators (CELMoDs) are attractive modalities to specifically target hitherto undruggable oncoproteins.We developed the first c-Myc degrader GT19630 (GT19715, the salt form of GT19630). We tested it in cell-free, cellular assays and in animal studies.GT19630 effectively degraded oncogenic c-Myc protein (IC50 = 1.5 nM) in HL-60 cells. C-Myc was effectively pulled down by biotinylated GT19630 in a cell-free, in vitro affinity purification assay; and a proteasome inhibitor ixazomib completely blocked c-Myc degradation. IC50 of GT19715 in HL-60 cells was 1.8 nM, being considerably lower than 40.2 nM, an IC50 of normal myeloid progenitors in CFU assay, suggesting a therapeutic window. GT19630 shares chemical properties with other CELMoDs and proteomic analyses revealed degradation of translation termination factor G1 to S phase transition proteins 1 (GSPT1), an important factor in LSC survival (Surka et al. Blood 2021). Indeed, GT19630 effectively degrades GSPT1 along with complete degradation of c-Myc in a xenograft model with HL-60 cells, and inhibits tumor growth at a dose as low as 0.3 mg/kg/bid. GT19630 had no effect on normal myeloid lineages in rats at 6 mg/kg. GT19715 eliminates circulating blasts and prolongs survival in the c-Myc-driven systemic Daudi leukemia/lymphoma model. Importantly, GT19715 induces cell killing independent of TP53 status, and baseline c-Myc protein levels significantly correlated with sensitivity to GT19715 in MOLM-13 cells with CRISPR engineered knockout or mutations of TP53 (R2 = 0.86, P = 0.02). We found that MV4;11 ven resistant (VR) cells demonstrated elevated protein levels of c-Myc, and GSPT1 and exhibited greater sensitivity to GT19715compared to ven-sensitive parental cells. Finally, GT19715 significantly reduced human CD45+ AML blasts compared to vehicle control in vivo in an AML PDX model.First results with the novel dual c-Myc/GSPT1 degrader GT19715 demonstrate promising preclinical anti-lymphoma and -leukemia efficacy, providing rationale for its clinical development.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
2秒前
TU发布了新的文献求助10
4秒前
现代鱼发布了新的文献求助10
4秒前
量子星尘发布了新的文献求助10
5秒前
Kawhi完成签到,获得积分10
5秒前
5秒前
7秒前
Hu完成签到,获得积分10
8秒前
9秒前
爱河发布了新的文献求助10
9秒前
欢喜大地发布了新的文献求助10
9秒前
9秒前
ding应助YanuoK采纳,获得10
12秒前
12秒前
wind完成签到,获得积分10
13秒前
eulota发布了新的文献求助10
13秒前
科研刘完成签到 ,获得积分10
13秒前
啰啰完成签到 ,获得积分10
15秒前
16秒前
16秒前
dmm发布了新的文献求助10
16秒前
17秒前
17秒前
18秒前
大模型应助科研通管家采纳,获得10
18秒前
斯文败类应助科研通管家采纳,获得10
18秒前
Orange应助科研通管家采纳,获得10
18秒前
我是老大应助科研通管家采纳,获得10
18秒前
wanci应助科研通管家采纳,获得10
18秒前
FashionBoy应助科研通管家采纳,获得10
18秒前
NexusExplorer应助科研通管家采纳,获得10
18秒前
深情安青应助科研通管家采纳,获得10
18秒前
852应助科研通管家采纳,获得10
19秒前
搜集达人应助科研通管家采纳,获得10
19秒前
烟花应助科研通管家采纳,获得10
19秒前
Meyako应助科研通管家采纳,获得10
19秒前
19秒前
19秒前
赘婿应助科研通管家采纳,获得10
19秒前
北一发布了新的文献求助10
22秒前
高分求助中
(应助此贴封号)【重要!!请各位详细阅读】【科研通的精品贴汇总】 10000
Voyage au bout de la révolution: de Pékin à Sochaux 700
血液中补体及巨噬细胞对大肠杆菌噬菌体PNJ1809-09活性的影响 500
Methodology for the Human Sciences 500
First Farmers: The Origins of Agricultural Societies, 2nd Edition 500
Simulation of High-NA EUV Lithography 400
International socialism & Australian labour : the Left in Australia, 1919-1939 400
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 4325279
求助须知:如何正确求助?哪些是违规求助? 3840252
关于积分的说明 12003814
捐赠科研通 3481134
什么是DOI,文献DOI怎么找? 1909404
邀请新用户注册赠送积分活动 954473
科研通“疑难数据库(出版商)”最低求助积分说明 855707