Verma Kshitij, Zang Tianzhu, Gupta Nehal, Penning Trevor M, Trippier Paul C
Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, School of Pharmacy , Amarillo, Texas 79106, United States.
Center of Excellence in Environmental Toxicology, Department of Systems Pharmacology & Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania 19104-6160, United States.
ACS Med Chem Lett. 2016 Jun 22;7(8):774-9. doi: 10.1021/acsmedchemlett.6b00163. eCollection 2016 Aug 11.
We report the design, synthesis, and evaluation of potent and selective inhibitors of aldo-keto reductase 1C3 (AKR1C3), an important enzyme in the regulatory pathway controlling proliferation, differentiation, and apoptosis in myeloid cells. Combination treatment with the nontoxic AKR1C3 inhibitors and etoposide or daunorubicin in acute myeloid leukemia cell lines, elicits a potent adjuvant effect, potentiating the cytotoxicity of etoposide by up to 6.25-fold and the cytotoxicity of daunorubicin by >10-fold. The results validate AKR1C3 inhibition as a common adjuvant target across multiple AML subtypes. These compounds in coadministration with chemotherapeutics in clinical use enhance therapeutic index and may avail chemotherapy as a treatment option to the pediatric and geriatric population currently unable to tolerate the side effects of cancer drug regimens.
我们报告了醛酮还原酶1C3（AKR1C3）强效和选择性抑制剂的设计、合成及评估，AKR1C3是控制髓系细胞增殖、分化和凋亡的调节途径中的一种重要酶。在急性髓系白血病细胞系中，将无毒的AKR1C3抑制剂与依托泊苷或柔红霉素联合治疗，可产生强效佐剂效应，使依托泊苷的细胞毒性增强高达6.25倍，柔红霉素的细胞毒性增强超过10倍。结果证实抑制AKR1C3是多种急性髓系白血病亚型的共同佐剂靶点。这些化合物与临床使用的化疗药物联合给药可提高治疗指数，并可能为目前无法耐受癌症药物治疗方案副作用的儿童和老年人群提供化疗作为一种治疗选择。
