title: OSU-T315: a novel targeted therapeutic that antagonizes AKT membrane localization and activation of chronic lymphocytic leukemia cells.
abstract: Aberrant regulation of endogenous survival pathways plays a major role in progression of chronic lymphocytic leukemia (CLL). Signaling via conjugation of surface receptors within the tumor environmental niche activates survival and proliferation pathways in CLL. Of these, the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway appears to be pivotal to support CLL pathogenesis, and pharmacologic inhibitors targeting this axis have shown clinical activity. Here we investigate OSU-T315, a compound that disrupts the PI3K/AKT pathway in a novel manner. Dose-dependent selective cytotoxicity by OSU-T315 is noted in both CLL-derived cell lines and primary CLL cells relative to normal lymphocytes. In contrast to the highly successful Bruton's tyrosine kinase and PI3K inhibitors that inhibit B-cell receptor (BCR) signaling pathway at proximal kinases, OSU-T315 directly abrogates AKT activation by preventing translocation of AKT into lipid rafts without altering the activation of receptor-associated kinases. Through this mechanism, the agent triggers caspase-dependent apoptosis in CLL by suppressing BCR, CD49d, CD40, and Toll-like receptor 9-mediated AKT activation in an integrin-linked kinase-independent manner. In vivo, OSU-T315 attains pharmacologically active drug levels and significantly prolongs survival in the TCL1 mouse model. Together, our findings indicate a novel mechanism of action of OSU-T315 with potential therapeutic application in CLL.
authors.affiliation: Department of Internal Medicine, Division of Hematology, Wexner Medical Center.
authors.forename: Ta-Ming
authors.initials: TM
authors.lastname: Liu
authors.affiliation: Pharmacoanalytical Shared Resource, Comprehensive Cancer Center.
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Ling
authors.affiliation: Department of Internal Medicine, Division of Hematology, Wexner Medical Center.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Woyach
authors.affiliation: Department of Internal Medicine, Division of Hematology, Wexner Medical Center.
authors.forename: Kyle
authors.initials: K
authors.lastname: Beckwith
authors.affiliation: Department of Internal Medicine, Division of Hematology, Wexner Medical Center.
authors.forename: Yuh-Ying
authors.initials: YY
authors.lastname: Yeh
authors.affiliation: Department of Internal Medicine, Division of Hematology, Wexner Medical Center.
authors.forename: Erin
authors.initials: E
authors.lastname: Hertlein
authors.affiliation: Center for Biostatistics.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Center for Biostatistics.
authors.forename: Amy
authors.initials: A
authors.lastname: Lehman
authors.affiliation: Department of Internal Medicine, Division of Hematology, Wexner Medical Center.
authors.forename: Farrukh
authors.initials: F
authors.lastname: Awan
authors.affiliation: Department of Internal Medicine, Division of Hematology, Wexner Medical Center.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Jones
authors.affiliation: Department of Internal Medicine, Division of Hematology, Wexner Medical Center.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Andritsos
authors.affiliation: Department of Internal Medicine, Division of Hematology, Wexner Medical Center.
authors.forename: Kami
authors.initials: K
authors.lastname: Maddocks
authors.affiliation: Department of Internal Medicine, Division of Hematology, Wexner Medical Center.
authors.forename: Jessica
authors.initials: J
authors.lastname: MacMurray
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, and.
authors.forename: Santosh B
authors.initials: SB
authors.lastname: Salunke
authors.affiliation: Department of Internal Medicine, Division of Hematology, Wexner Medical Center, Department of Medical Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH.
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, and.
authors.forename: Mitch A
authors.initials: MA
authors.lastname: Phelps
authors.affiliation: Department of Internal Medicine, Division of Hematology, Wexner Medical Center, Department of Medical Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH.
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.affiliation: Department of Internal Medicine, Division of Hematology, Wexner Medical Center, Department of Medical Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D051057:Proto-Oncogene Proteins c-akt