School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA.
Bioorg Med Chem Lett. 2013 Jun 1;23(11):3283-7. doi: 10.1016/j.bmcl.2013.03.108. Epub 2013 Apr 4.
Current chemotherapy regimens are comprised mostly of single-target drugs which are often plagued by toxic side effects and resistance development. A pharmacological strategy for circumventing these drawbacks could involve designing multivalent ligands that can modulate multiple targets while avoiding the toxicity of a single-targeted agent. Two attractive targets, histone deacetylase (HDAC) and topoisomerase I (Topo I), are cellular modulators that can broadly arrest cancer proliferation through a range of downstream effects. Both are clinically validated targets with multiple inhibitors in therapeutic use. We describe herein the design and synthesis of dual-acting histone deacetylase-topoisomerase I inhibitors. We also show that these dual-acting agents retain activity against HDAC and Topo I, and potently arrest cancer proliferation.
目前的化疗方案主要由单靶点药物组成，这些药物常常受到毒性副作用和耐药性发展的困扰。一种规避这些缺点的药理学策略可能涉及设计多价配体，这些配体可以调节多个靶点，同时避免单靶点药物的毒性。组蛋白去乙酰化酶（HDAC）和拓扑异构酶 I（Topo I）是两种有吸引力的靶点，它们是细胞调节剂，可以通过一系列下游效应广泛阻止癌细胞增殖。这两个靶点都是经过临床验证的靶点，有多种抑制剂在治疗中使用。本文描述了双作用组蛋白去乙酰化酶-拓扑异构酶 I 抑制剂的设计和合成。我们还表明，这些双作用试剂保留了对 HDAC 和 Topo I 的活性，并能有效地抑制癌症的增殖。
