title: Structure-Based Screen Identifies a Potent Small Molecule Inhibitor of Stat5a/b with Therapeutic Potential for Prostate Cancer and Chronic Myeloid Leukemia.
abstract: Bypassing tyrosine kinases responsible for Stat5a/b phosphorylation would be advantageous for therapy development for Stat5a/b-regulated cancers. Here, we sought to identify small molecule inhibitors of Stat5a/b for lead optimization and therapy development for prostate cancer and Bcr-Abl-driven leukemias. In silico screening of chemical structure databases combined with medicinal chemistry was used for identification of a panel of small molecule inhibitors to block SH2 domain-mediated docking of Stat5a/b to the receptor-kinase complex and subsequent phosphorylation and dimerization. We tested the efficacy of the lead compound IST5-002 in experimental models and patient samples of two known Stat5a/b-driven cancers, prostate cancer and chronic myeloid leukemia (CML). The lead compound inhibitor of Stat5-002 (IST5-002) prevented both Jak2 and Bcr-Abl-mediated phosphorylation and dimerization of Stat5a/b, and selectively inhibited transcriptional activity of Stat5a (IC50 = 1.5μmol/L) and Stat5b (IC50 = 3.5 μmol/L). IST5-002 suppressed nuclear translocation of Stat5a/b, binding to DNA and Stat5a/b target gene expression. IST5-002 induced extensive apoptosis of prostate cancer cells, impaired growth of prostate cancer xenograft tumors, and induced cell death in patient-derived prostate cancers when tested ex vivo in explant organ cultures. Importantly, IST5-002 induced robust apoptotic death not only of imatinib-sensitive but also of imatinib-resistant CML cell lines and primary CML cells from patients. IST5-002 provides a lead structure for further chemical modifications for clinical development for Stat5a/b-driven solid tumors and hematologic malignancies.
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Liao
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Lei
authors.initials: L
authors.lastname: Gu
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Jenny
authors.initials: J
authors.lastname: Vergalli
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Samanta A
authors.initials: SA
authors.lastname: Mariani
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Marco
authors.initials: M
authors.lastname: De Dominici
authors.affiliation: Department of Biochemistry, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Lokareddy
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Ayush
authors.initials: A
authors.lastname: Dagvadorj
authors.affiliation: School of Pharmacy, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Puranik
authors.initials: P
authors.lastname: Purushottamachar
authors.affiliation: Department of Pathology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Peter A
authors.initials: PA
authors.lastname: McCue
authors.affiliation: Department of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Edouard
authors.initials: E
authors.lastname: Trabulsi
authors.affiliation: Department of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Costas D
authors.initials: CD
authors.lastname: Lallas
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Elyse
authors.initials: E
authors.lastname: Ellsworth
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Shauna
authors.initials: S
authors.lastname: Blackmon
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Adam
authors.initials: A
authors.lastname: Ertel
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Paolo
authors.initials: P
authors.lastname: Fortina
authors.affiliation: Division of Biostatistics, Department of Pharmacology and Experimental Therapeutics, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Leiby
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Guanjun
authors.initials: G
authors.lastname: Xia
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Pathology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Hallgeir
authors.initials: H
authors.lastname: Rui
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: David T
authors.initials: DT
authors.lastname: Hoang
authors.affiliation: Department of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Leonard G
authors.initials: LG
authors.lastname: Gomella
authors.affiliation: Department of Biochemistry, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Gino
authors.initials: G
authors.lastname: Cingolani
authors.affiliation: School of Pharmacy, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Vincent
authors.initials: V
authors.lastname: Njar
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia.
authors.forename: Nagarajan
authors.initials: N
authors.lastname: Pattabiraman
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Bruno
authors.initials: B
authors.lastname: Calabretta
authors.affiliation: Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. mnevalainen@mcw.edu.
authors.forename: Marja T
authors.initials: MT
authors.lastname: Nevalainen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D016208:Databases, Factual; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D015870:Gene Expression; D020869:Gene Expression Profiling; D017930:Genes, Reporter; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D055503:Protein Multimerization; D021281:Quantitative Structure-Activity Relationship; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries; D046509:Tissue Culture Techniques; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494095:STAT5B protein, human; D054852:Small Molecule Libraries; D025521:Tumor Suppressor Proteins