New Insights Into DNA Helicases as Druggable Targets for Cancer Therapy.
New Insights Into DNA Helicases as Druggable Targets for Cancer Therapy.
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对DNA解旋酶作为癌症治疗的可药靶标的新见解。
DOI：
10.3389/fmolb.2018.00059
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发表时间：
2018
影响因子：
5
通讯作者：
Brosh RM Jr
中科院分区：
文献类型：
--
作者：
Datta A;Brosh RM Jr
阻止DNA损伤反应机制功能的小分子被认为有助于增强化疗或电离辐射治疗的DNA损伤效应，通过损害积累复制病变的快速分裂细胞的增殖能力来对抗癌症。化学致死性或遗传合成致死性是个性化医疗中一个很有前途的领域，但仍有待优化。癌症治疗的新目标是DNA解绕酶，即解旋酶。解旋酶在核酸代谢的各个方面都起着至关重要的作用。我们和其他人利用生物化学和基于细胞的方法，通过复合筛选研究了小分子靶向解旋酶功能的抑制。小分子诱导的DNA解旋酶的捕获可能代表了一种普遍的机制，例如某些拓扑异构酶和PARP抑制剂会产生毒性后果，特别是在快速分裂的癌细胞中。从更广泛的DNA修复抑制剂领域和从DNA解旋酶的结构和生化研究中收集到的新信息来看，我们预测一种新兴的识别有用的解旋酶相互作用化合物的策略将是基于结构的分子对接接口和计算方法。解旋酶抑制剂药物的效力、特异性、耐药性和生物利用度以及将这些化合物靶向到各自解旋酶起作用的亚细胞区室必须加以解决。除了癌症治疗之外，这一领域的持续和新的发展可能会导致发现解旋酶相互作用的化合物，这些化合物可以化学地拯救临床相关的解旋酶错义突变蛋白或激活野生型DNA解旋酶的催化功能，这可能具有新的治疗应用。
Small molecules that deter the functions of DNA damage response machinery are postulated to be useful for enhancing the DNA damaging effects of chemotherapy or ionizing radiation treatments to combat cancer by impairing the proliferative capacity of rapidly dividing cells that accumulate replicative lesions. Chemically induced or genetic synthetic lethality is a promising area in personalized medicine, but it remains to be optimized. A new target in cancer therapy is DNA unwinding enzymes known as helicases. Helicases play critical roles in all aspects of nucleic acid metabolism. We and others have investigated small molecule targeted inhibition of helicase function by compound screens using biochemical and cell-based approaches. Small molecule-induced trapping of DNA helicases may represent a generalized mechanism exemplified by certain topoisomerase and PARP inhibitors that exert poisonous consequences, especially in rapidly dividing cancer cells. Taking the lead from the broader field of DNA repair inhibitors and new information gleaned from structural and biochemical studies of DNA helicases, we predict that an emerging strategy to identify useful helicase-interacting compounds will be structure-based molecular docking interfaced with a computational approach. Potency, specificity, drug resistance, and bioavailability of helicase inhibitor drugs and targeting such compounds to subcellular compartments where the respective helicases operate must be addressed. Beyond cancer therapy, continued and new developments in this area may lead to the discovery of helicase-interacting compounds that chemically rescue clinically relevant helicase missense mutant proteins or activate the catalytic function of wild-type DNA helicases, which may have novel therapeutic application.
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影响因子：
7.3
作者：
Faucher, AM;White, PW;Fazal, G
通讯作者：
Fazal, G
影响因子：
5.6
作者：
Awate S;Brosh RM Jr
通讯作者：
Brosh RM Jr
DOI：
10.1073/pnas.030539597
发表时间：
2000-02-15
影响因子：
11.1
作者：
Chong, JPJ;Hayashi, MK;Stillman, B
通讯作者：
Stillman, B
DOI：
10.1073/pnas.1213981110
发表时间：
2013-02-19
影响因子：
11.1
作者：
Abdulrahman, Wassim;Iltis, Izarn;Poterszman, Arnaud
通讯作者：
Poterszman, Arnaud
影响因子：
3.1
作者：
Belon CA;Frick DN
通讯作者：
Frick DN