Prospects for Clinical Development of Stat5 Inhibitor IST5-002: High Transcriptomic Specificity in Prostate Cancer and Low Toxicity In Vivo.
Prospects for Clinical Development of Stat5 Inhibitor IST5-002: High Transcriptomic Specificity in Prostate Cancer and Low Toxicity In Vivo.
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DOI：
10.3390/cancers12113412
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发表时间：
2020-11-18
期刊：
影响因子：
5.2
通讯作者：
Nevalainen MT
中科院分区：
文献类型：
--
作者：
Maranto C;Udhane V;Jia J;Verma R;Müller-Newen G;LaViolette PS;Pereckas M;Sabharwal L;Terhune S;Pattabiraman N;Njar VCO;Imig JD;Wang L;Nevalainen MT
对于蛋白质Stat5，医学上对新型高效的药理抑制剂药物存在需求，这些药物需具有口服生物利用度，用于治疗几种不同的癌症。先前的研究已经确定了Stat5在前列腺癌向转移性疾病的分子和临床进展以及几种白血病和血液疾病的发病机制中起着关键作用。我们的团队已经开发出一种针对Stat5的高效药理抑制剂IST5 - 002，它针对癌细胞中Stat5激活过程中的两个关键步骤。在目前的研究中，我们评估了IST5 - 002的特性，以便进一步将其开发为一种抗癌药物。我们评估了IST5 - 002是否影响前列腺癌中Stat5的靶基因，更精确地确定了其作用机制，并研究了其初始毒性，以此作为进一步开发的基础，使其能够进入患者的临床试验。我们的研究支持对IST5 - 002化合物进行优化，以提高其口服生物利用度并用于临床开发。
Stat5在寻找前列腺癌（PC）和造血疾病的新疗法方面具有重要意义。我们评估了Stat5a/b抑制剂IST5 - 002（IST5）在PC中的转录组特异性，更精确地确定了其作用机制，并研究了IST5在体内的毒性，以便进一步优化用于临床开发。通过RNA - seq分析评估了IST5与基因敲低Stat5的转录组特异性，结果显示皮尔逊相关系数在0.98 - 0.99之间，具有高度相似性。在两个独立但互补的实验中评估了IST5与其不含磷酸基团的衍生物在抑制Stat5方面的效力。在无细胞实验中研究了IST5对激酶的抑制活性，随后在基于细胞的实验中进行了更有针对性的评估。IST5对54种激酶没有特异性抑制活性，但能抑制PC细胞中Stat5的磷酸化和随后的二聚化。磷酸基团对IST5在细胞中的生物活性并非关键。在小鼠中进行了IST5的急性、亚慢性和慢性毒性研究。IST5没有引起任何显著的毒性作用或血液指标的变化。目前的研究支持进一步优化IST5的口服生物利用度，以便用于实体瘤、血液和骨髓增殖性疾病治疗的临床开发。
There is an unmet medical need for new and potent pharmacological inhibitor drugs for the protein Stat5 that would be orally bioavailable for treatment of several different cancers. Previous work has established a critical role for Stat5 in molecular and clinical progression of prostate cancer to metastatic disease and in the pathogenesis of several leukemias and blood-based disorders. Our group has developed a potent pharmacological inhibitor for Stat5, IST5-002, which targets two critical steps in the activation process of Stat5 in cancer cells. In the present work, we evaluated the characteristics of IST5-002 for further development into a cancer drug. We evaluated whether IST5-002 affects the Stat5 targets genes in prostate cancer, defined more closely its mechanisms of action, and investigated its initial toxicity as the basis for further development in order to enable its entrance into clinical testing in patients. Our study supports optimization of IST5-002 compound for oral bioavailability and for clinical development. Stat5 is of significant interest in the search for new therapeutics for prostate cancer (PC) and hematopoietic disorders. We evaluated the transcriptomic specificity of the Stat5a/b inhibitor IST5-002 (IST5) in PC, defined more closely its mechanisms of action, and investigated the in vivo toxicity of IST5 for further optimization for clinical development. The transcriptomic specificity of IST5 vs. genetic Stat5 knockdown was evaluated by RNA-seq analysis, which showed high similarity with the Pearson correlation coefficient ranging from 0.98–0.99. The potency of IST5 vs. its derivative lacking the phosphate group in suppressing Stat5 was evaluated in two separate but complementary assays. The inhibitory activity of IST5 against kinases was investigated in cell-free assays followed by more focused evaluation in a cell-based assay. IST5 has no specific inhibitory activity against 54 kinases, while suppressing Stat5 phosphorylation and subsequent dimerization in PC cells. The phosphate group was not critical for the biological activity of IST5 in cells. The acute, sub-chronic and chronic toxicity studies of IST5 were carried out in mice. IST5 did not cause any significant toxic effects or changes in the blood profiles. The present work supports further optimization of IST5 for oral bioavailability for clinical development for therapies for solid tumors, hematological and myeloproliferative disorders.
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影响因子：
4.6
作者：
Elumalai, Nagarajan;Berg, Angela;Berg, Thorsten
通讯作者：
Berg, Thorsten
影响因子：
5.7
作者：
Hoang DT;Gu L;Liao Z;Shen F;Talati PG;Koptyra M;Tan SH;Ellsworth E;Gupta S;Montie H;Dagvadorj A;Savolainen S;Leiby B;Mirtti T;Merry DE;Nevalainen MT
通讯作者：
Nevalainen MT
影响因子：
14.9
作者：
Frankish A;Diekhans M;Ferreira AM;Johnson R;Jungreis I;Loveland J;Mudge JM;Sisu C;Wright J;Armstrong J;Barnes I;Berry A;Bignell A;Carbonell Sala S;Chrast J;Cunningham F;Di Domenico T;Donaldson S;Fiddes IT;García Girón C;Gonzalez JM;Grego T;Hardy M;Hourlier T;Hunt T;Izuogu OG;Lagarde J;Martin FJ;Martínez L;Mohanan S;Muir P;Navarro FCP;Parker A;Pei B;Pozo F;Ruffier M;Schmitt BM;Stapleton E;Suner MM;Sycheva I;Uszczynska-Ratajczak B;Xu J;Yates A;Zerbino D;Zhang Y;Aken B;Choudhary JS;Gerstein M;Guigó R;Hubbard TJP;Kellis M;Paten B;Reymond A;Tress ML;Flicek P
通讯作者：
Flicek P
DOI：
10.1158/1078-0432.ccr-08-0979
发表时间：
2008-10-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Dagvadorj A;Tan SH;Liao Z;Cavalli LR;Haddad BR;Nevalainen MT
通讯作者：
Nevalainen MT
影响因子：
46.9
作者：
通讯作者：
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