title: Pyoluteorin derivatives induce Mcl-1 degradation and apoptosis in hematological cancer cells.
abstract: Mcl-1, a pro-survival member of the Bcl-2 protein family, is an attractive target for cancer therapy. We have recently identified the natural product marinopyrrole A (maritoclax) as a novel small molecule Mcl-1 inhibitor. Here, we describe the structure-activity relationship study of pyoluteorin derivatives based on maritoclax. To date, we synthesized over 30 derivatives of maritoclax and evaluated their inhibitory actions and cytotoxicity toward Mcl-1-dependent cell lines. As a result, several functional groups were identified in the pyoluteorin motif that significantly potentiate biological activity. A number of such derivatives, KS04 and KS18, interacted with Mcl-1 in a conserved fashion according to NMR spectroscopy and molecular modeling. KS04 and KS18 induced apoptosis selectively in Mcl-1-dependent but not Bcl-2-dependent K562 cells through selective Mcl-1 down-regulation, and synergistically enhanced apoptosis in combination with ABT-737. Moreover, the intraperitoneal administration of KS18 (10 mg/kg/d) and ABT-737 (20 mg/kg/d) significantly suppressed the growth of ABT-737-resistant HL-60 xenografts in nude mice without apparent toxicity. Overall, we identified the pharmacophore of pyoluteorin derivatives that act as potent and promising Mcl-1 antagonists against Mcl-1-dependent hematological cancers.
authors.affiliation: a Department of Pediatrics ; Pennsylvania State University College of Medicine ; Hershey , PA USA.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Doi
authors.forename: Krishne
authors.initials: K
authors.lastname: Gowda
authors.forename: Qiang
authors.initials: Q
authors.lastname: Liu
authors.forename: Jyh-Ming
authors.initials: JM
authors.lastname: Lin
authors.forename: Shen-Shu
authors.initials: SS
authors.lastname: Sung
authors.forename: Christopher
authors.initials: C
authors.lastname: Dower
authors.forename: David
authors.initials: D
authors.lastname: Claxton
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Loughran
authors.forename: Shantu
authors.initials: S
authors.lastname: Amin
authors.forename: Hong-Gang
authors.initials: HG
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D019337:Hematologic Neoplasms / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D010636:Phenols / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D059748:Proteolysis / Q000187:drug effects; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010636:Phenols; D011758:Pyrroles; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C528298:marinopyrrole A; C095503:pyoluteorin
keywords: ABTR, ABT-737 resistant; AML, Acute Myeloid Leukemia; AUCinf, area under curve extrapolated to time infinity; AUClast, area under curve until last observed timepoint; Apoptosis; BH3, Bcl-2 homology domain 3; Bcl-2 family; Bcl-2, B-cell lymphoma-2; CHX, Cycloheximide; CL, rate of plasma clearance; Cmax, maximal plasma concentration; EC50, Half maximal effective concentration; IRES, Internal ribosome entry site; LD50, median lethal dose; MTD, Maximal tolerated dose; Mcl-1; Mcl-1, Myeloid cell leukemia-1; NMR, Nuclear magnetic resonance; PARP, Poly (ADP-ribose) polymerase; SAR, Structure-activity relationship; T1/2, plasma half-life; Tmax, time to maximal plasma concentration; VD, Volume of distribution; i.p., Intraperitoneal; leukemia; lymphoma; maritoclax; multiple myeloma; pyoluteorin