title: Hydroxyquinoline-derived compounds and analoguing of selective Mcl-1 inhibitors using a functional biomarker.
abstract: Anti-apoptotic Bcl-2 family proteins are important oncology therapeutic targets. To date, BH3 mimetics that abrogate anti-apoptotic activity have largely been directed at Bcl-2 and/or Bcl-xL. One observed mechanism of resistance to these inhibitors is increased Mcl-1 levels in cells exposed to such therapeutics. For this reason, and because Mcl-1 is important in the onset of lymphoid, myeloid, and other cancers, it has become a target of great interest. However, small molecule inhibitors displaying potency and selectivity for Mcl-1 are lacking. Identifying such compounds has been challenging due to difficulties in translating the target selectivity observed at the biochemical level to the cellular level. Herein we report the results of an HTS strategy coupled with directed hit optimization. Compounds identified have selective Mcl-1 inhibitory activity with greater than 100-fold reduced affinity for Bcl-xL. The selectivity of these compounds at the cellular level was validated using BH3 profiling, a novel personalized diagnostic approach. This assay provides an important functional biomarker that allows for the characterization of cells based upon their dependencies on various anti-apoptotic Bcl-2 proteins. We demonstrate that cells dependent on Mcl-1 or Bcl-2/Bcl-xL for survival are commensurately responsive to compounds that genuinely target those proteins. The identification of compound 9 with uniquely validated and selective Mcl-1 inhibitory activity provides a valuable tool to those studying the intrinsic apoptosis pathway and highlights an important approach in the development of a first-in-class cancer therapeutic.
authors.affiliation: Eutropics Pharmaceuticals, 767C Concord Avenue, Cambridge, MA 02138, United States.
authors.forename: David J
authors.initials: DJ
authors.lastname: Richard
authors.forename: Ryan
authors.initials: R
authors.lastname: Lena
authors.forename: Thomas
authors.initials: T
authors.lastname: Bannister
authors.forename: Noel
authors.initials: N
authors.lastname: Blake
authors.forename: William E
authors.initials: WE
authors.lastname: Pierceall
authors.forename: Nicole E
authors.initials: NE
authors.lastname: Carlson
authors.forename: Christina Eberhart
authors.initials: CE
authors.lastname: Keller
authors.forename: Marcel
authors.initials: M
authors.lastname: Koenig
authors.forename: Yuanjun
authors.initials: Y
authors.lastname: He
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Minond
authors.forename: Jitendra
authors.initials: J
authors.lastname: Mishra
authors.forename: Michael
authors.initials: M
authors.lastname: Cameron
authors.forename: Timothy
authors.initials: T
authors.lastname: Spicer
authors.forename: Peter
authors.initials: P
authors.lastname: Hodder
authors.forename: Michael H
authors.initials: MH
authors.lastname: Cardone
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D015415:Biomarkers / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D018922:HL-60 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D006912:Hydroxyquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D006912:Hydroxyquinolines; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D045304:Cytochromes c
keywords: Apoptosis; Biomarkers; Cell-based activity; Mcl-1; Oncology