HSC70 modulators(heat shock protein family A (Hsp70) member 8 modulators)、HSPA5调节剂(78kDa葡萄糖调节蛋白调节剂)、HSPA9调节剂(heat shock protein family A (Hsp70) member 9 modulators)

治疗领域

肿瘤泌尿生殖系统疾病

在研适应症

子宫内膜癌

非在研适应症-

原研机构

University of Oklahoma

在研机构

University of Oklahoma

非在研机构-

最高研发阶段临床1期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

登录后查看时间轴

关联

100 项与 SHetA2 相关的临床结果

登录后查看更多信息

100 项与 SHetA2 相关的转化医学

登录后查看更多信息

100 项与 SHetA2 相关的专利（医药）

登录后查看更多信息

项与 SHetA2 相关的文献（医药）

2024-01-01·Gynecologic Oncology

Manipulation of metabolic responses enhances SHetA2 efficacy without toxicity in cervical cancer cell lines and xenografts

Article

作者: Benbrook, Doris Mangiaracina ; Lightfoot, Stanley ; Rai, Rajani

OBJECTIVEThe high frequency of cervical cancer recurrence after primary therapy necessitates alternative treatments. High-risk human papillomavirus (HR-HPV) causes cervical cancer and it's continued presence supports elevated metabolism, proliferation and survival of cancer cells. The low-to-no toxicity new investigational drug, SHetA2, counteracts high-risk human papillomavirus (HR-HPV) effects on cell proliferation and survival in cervical cancer cells and xenograft tumors by disrupting heat shock protein 70 chaperone protection of oncogenic proteins. Our objective was to study the involvement of metabolism in SHetA2 effects on cervical cancer cells and tumors.METHODSSHetA2-mediated proteomic and metabolic effects were measured in HR-HPV-positive CaSKi and SiHa and HR-HPV-negative C-33 A cervical cancer cell lines. Combined treatment with 2-deoxyglucose (2-DG) was evaluated in cell culture and SiHa xenografts.RESULTSSHetA2 inhibited oxidative phosphorylation (OxPhos) and altered levels of proteins involved in metabolism, protein synthesis, and DNA replication and repair. Cervical cancer cells responded by elevating glycolysis. Inhibition of the glycolytic responses using galactose media or 2-DG increased SHetA2 sensitivity of two HR-HPV-positive, but not an HR-HPV-negative cervical cancer cell line. Interaction of 2-DG and SHetA2 was synergistic in HR-HPV positive cell lines in association with augmentation of SHetA2 ATP reduction, but not SHetA2 DNA damage induction. These results were verified in a SiHa xenograft tumor model without evidence of toxicity.CONCLUSIONSCompensatory glycolysis counteracts OxPhos inhibition in SHetA2-treated HR-HPV-positive cervical cancer cell lines. Prevention of compensatory glycolysis with 2-DG or another glycolysis inhibitor has the potential to improve SHetA2 therapy without toxicity.

2020-08-15·International Journal of Cancer1区 · 医学

Novel ovarian cancer maintenance therapy targeted at mortalin and mutant p53

1区 · 医学

Article

作者: Elayapillai, Sugantha P. ; Kennedy, Amy L. ; Benbrook, Doris M. ; Lightfoot, Stanley A. ; Ramraj, Satish K. ; Zhao, Yan D. ; Isingizwe, Zitha R. ; Pelikan, Richard C.

Current ovarian cancer maintenance therapy is limited by toxicity and no proven impact on overall survival. To study a maintenance strategy targeted at missense mutant p53, we hypothesized that the release of mutant p53 from mortalin inhibition by the SHetA2 drug combined with reactivation of mutant p53 with the PRIMA‐1MET drug inhibits growth and tumor establishment synergistically in a mutant‐p53 dependent manner. The Cancer Genome Atlas (TCGA) data and serous ovarian tumors were evaluated for TP53 and HSPA9/mortalin status. SHetA2 and PRIMA‐1MET were tested in ovarian cancer cell lines and fallopian tube secretory epithelial cells using isobolograms, fluorescent cytometry, Western blots and ELISAs. Drugs were administered to mice after peritoneal injection of MESOV mutant p53 ovarian cancer cells and prior to tumor establishment, which was evaluated by logistic regression. Fifty‐eight percent of TP53 mutations were missense and there were no mortalin mutations in TCGA high‐grade serous ovarian cancers. Mortalin levels were sequentially increased in serous benign, borderline and carcinoma tumors. SHetA2 caused p53 nuclear and mitochondrial accumulation in cancer, but not in healthy, cells. Endogenous or exogenous mutant p53 increased SHetA2 resistance. PRIMA‐1MET decreased this resistance and interacted synergistically with SHetA2 in mutant and wild type p53‐expressing cell lines in association with elevated reactive oxygen species/ATP ratios. Tumor‐free rates in animals were 0% (controls), 25% (PRIMA1MET), 42% (SHetA2) and 67% (combination). SHetA2 (p = 0.004) and PRIMA1MET (p = 0.048) functioned additively in preventing tumor development with no observed toxicity. These results justify the development of SHetA2 and PRIMA‐1MET alone and in combination for ovarian cancer maintenance therapy.

2020-06-01·Journal of Pharmaceutical Sciences

Vaginal Suppositories Containing SHetA2 to Treat Cervical Dysplasia: Pharmacokinetics of Daily Doses and Preliminary Safety Profile

Article

作者: Mahjabeen, Sanjida ; Hatipoglu, Manolya Kukut ; Garcia-Contreras, Lucila ; Garcia-Contreras, David ; Benbrook, Doris M ; Kosanke, Stanley D

SHetA2 is a new drug with potential to treat cervical dysplasia, but only 0.02% of the dose is absorbed into the cervix after oral administration. By contrast, 23.9% of the dose is absorbed into the cervix after vaginal administration. This study determines the pharmacokinetic and pharmacodynamic parameters after daily vaginal doses of SHetA2 in suppositories and assesses its safety. Daily dosed mice maintained therapeutic concentrations of SHetA2 in the cervix for 65 h. The steady-state area under the curve concentration versus time (AUC_cervix) after the last dose was similar to that after a single dose indicating that there was no drug accumulation in the cervix. By contrast, the maximum drug concentration (C_max-cervix) was smaller in the daily dosed group (52.19 μg/g) than after a single dose (121.84 μg/g), whereas the half-life (t_1/2-cervix) was also shorter in the daily dosed group (9.94 h) than after a single dose (23.32 h). Notably, daily vaginal doses of SHetA2 reduced the levels of cyclin D1 (the pharmacodynamic endpoint) to a larger extent (∼45%) than after the administration of a single dose (∼26%). No adverse effects were observed in the mice for the duration of the study; thus, daily vaginal doses of SHetA2 appear to be safe.

100 项与 SHetA2 相关的药物交易

登录后查看更多信息