Discovery of AZ0108, an orally bioavailable phthalazinone PARP inhibitor that blocks centrosome clustering.

Autor: Johannes JW; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Almeida L; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Daly K; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Ferguson AD; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Grosskurth SE; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Guan H; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Howard T; AstraZeneca R&D Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom., Ioannidis S; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Kazmirski S; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Lamb ML; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Larsen NA; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Lyne PD; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Mikule K; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Ogoe C; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Peng B; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Petteruti P; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Read JA; AstraZeneca R&D Building 310, Milton Science Park, Cambridge CB4 0WG, United Kingdom., Su N; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Sylvester M; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Throner S; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Wang W; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Wang X; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Wu J; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Ye Q; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Yu Y; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Zheng X; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States., Scott DA; AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2015 Dec 15; Vol. 25 (24), pp. 5743-7. Date of Electronic Publication: 2015 Oct 27.
DOI: 10.1016/j.bmcl.2015.10.079
Abstrakt: The propensity for cancer cells to accumulate additional centrosomes relative to normal cells could be exploited for therapeutic benefit in oncology. Following literature reports that suggested TNKS1 (tankyrase 1) and PARP16 may be involved with spindle structure and function and may play a role in suppressing multi-polar spindle formation in cells with supernumerary centrosomes, we initiated a phenotypic screen to look for small molecule poly (ADP-ribose) polymerase (PARP) enzyme family inhibitors that could produce a multi-polar spindle phenotype via declustering of centrosomes. Screening of AstraZeneca's collection of phthalazinone PARP inhibitors in HeLa cells using high-content screening techniques identified several compounds that produced a multi-polar spindle phenotype at low nanomolar concentrations. Characterization of these compounds across a broad panel of PARP family enzyme assays indicated that they had activity against several PARP family enzymes, including PARP1, 2, 3, 5a, 5b, and 6. Further optimization of these initial hits for improved declustering potency, solubility, permeability, and oral bioavailability resulted in AZ0108, a PARP1, 2, 6 inhibitor that potently inhibits centrosome clustering and is suitable for in vivo efficacy and tolerability studies.
(Copyright © 2015 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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