A Potent and Selective ULK1 Inhibitor Suppresses Autophagy and Sensitizes Cancer Cells to Nutrient Stress.
A Potent and Selective ULK1 Inhibitor Suppresses Autophagy and Sensitizes Cancer Cells to Nutrient Stress.
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DOI：
10.1016/j.isci.2018.09.012
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发表时间：
2018-10-26
期刊：
影响因子：
5.8
通讯作者：
MacKeigan JP
中科院分区：
文献类型：
--
作者：
Martin KR;Celano SL;Solitro AR;Gunaydin H;Scott M;O'Hagan RC;Shumway SD;Fuller P;MacKeigan JP
为了应对压力，癌细胞通过称为自噬的细胞再循环过程产生营养和能量，这可以促进生存和肿瘤进展。因此，自噬抑制已经成为一种潜在的癌症治疗策略。靶向ULK 1（一种重要的早期自噬调节因子）的抑制剂为靶向这种激酶以抑制自噬提供了概念证明;然而，这些抑制剂在其效力、选择性或细胞活性方面受到单独限制。在这项研究中，我们报告了两个小分子ULK 1抑制剂，ULK-100和ULK-101，并建立了上级效力和选择性超过一个值得注意的出版的抑制剂。此外，我们表明，ULK-101抑制自噬诱导和自噬通量响应于不同的刺激。最后，我们使用ULK-101来证明ULK 1抑制使KRAS突变型肺癌细胞对营养应激敏感。ULK-101是研究自噬在癌细胞中的作用和评估自噬抑制的治疗潜力的强大分子工具。与SBI-0206965相比，ULK-101具有更高的效力和选择性ULK-101抑制自噬囊泡的成核和周转ULK-101使KRAS驱动的肺癌细胞对营养限制敏感ULK-101是研究ULK 1和自噬功能的有价值的分子工具治疗;细胞生物学功能方面;癌症
In response to stress, cancer cells generate nutrients and energy through a cellular recycling process called autophagy, which can promote survival and tumor progression. Accordingly, autophagy inhibition has emerged as a potential cancer treatment strategy. Inhibitors targeting ULK1, an essential and early autophagy regulator, have provided proof of concept for targeting this kinase to inhibit autophagy; however, these are limited individually in their potency, selectivity, or cellular activity. In this study, we report two small molecule ULK1 inhibitors, ULK-100 and ULK-101, and establish superior potency and selectivity over a noteworthy published inhibitor. Moreover, we show that ULK-101 suppresses autophagy induction and autophagic flux in response to different stimuli. Finally, we use ULK-101 to demonstrate that ULK1 inhibition sensitizes KRAS mutant lung cancer cells to nutrient stress. ULK-101 represents a powerful molecular tool to study the role of autophagy in cancer cells and to evaluate the therapeutic potential of autophagy inhibition. ULK-101 has improved potency and selectivity when compared with SBI-0206965 ULK-101 inhibits both the nucleation of autophagic vesicles and turnover ULK-101 sensitizes KRAS-driven lung cancer cells to nutrient restriction ULK-101 is a valuable molecular tool to study the function of ULK1 and autophagy Therapeutics; Functional Aspects of Cell Biology; Cancer
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影响因子：
28.2
作者：
Karsli-Uzunbas G;Guo JY;Price S;Teng X;Laddha SV;Khor S;Kalaany NY;Jacks T;Chan CS;Rabinowitz JD;White E
通讯作者：
White E
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
10.5
作者：
Guo, Jessie Yanxiang;Chen, Hsin-Yi;White, Eileen
通讯作者：
White, Eileen
影响因子：
28.2
作者：
Lock R;Kenific CM;Leidal AM;Salas E;Debnath J
通讯作者：
Debnath J
影响因子：
3.3
作者：
Jung, Chang Hwa;Jun, Chang Bong;Kim, Do-Hyung
通讯作者：
Kim, Do-Hyung