A Buchwald-Hartwig Protocol to Enable Rapid Linker Exploration of Cereblon E3-Ligase PROTACs

被引：21
作者：
Hayhow, Thomas G. [1 ]
Borrows, Rachel E. A. [1 ]
Diene, Coura R. [1 ]
Fairley, Gary [2 ]
Fallan, Charlene [1 ]
Fillery, Shaun M. [1 ]
Scott, James S. [1 ]
Watson, David W. [1 ]
机构：
[1] AstraZeneca, Med Chem, Oncol R&D, Res & Early Dev, Cambridge Sci Pk,Unit 310 Darwin Bldg, Cambridge CB4 0WG, England
[2] AstraZeneca, Res & Early Dev, Oncol R&D, Med Chem, Macclesfield Campus,Etherow Bldg,Silk Rd Ind, Macclesfield SK10 2NA, Cheshire, England
来源：
CHEMISTRY-A EUROPEAN JOURNAL | 2020年 / 26卷 / 70期
关键词：
amination; cereblon; drug discovery; PEPPSI; PROTAC; N-HETEROCYCLIC CARBENE; PD-NHC PRECATALYST; MULTIPLE-MYELOMA; THALIDOMIDE; PEPPSI; CATALYST; DISEASE; DESIGN;
D O I：
10.1002/chem.202003137
中图分类号：
O6 [化学];
学科分类号：
0703 ;
摘要：
A palladium-catalysed Buchwald-Hartwig amination for lenalidomide-derived aryl bromides was optimised using high throughput experimentation (HTE). The substrate scope of the optimised conditions was evaluated for a range of alkyl- and aryl- amines and functionalised aryl bromides. The methodology allows access to new cereblon-based bifunctional proteolysis targeting chimeras with a reduced step count and improved yields.
引用
收藏
页码：16818 / 16823
页数：6
相关论文
共 38 条
  • [1] Andrew P., 2018, Patent No. [WO2018/102725A1, 2018102725, 2018102725A1]
  • [2] Molecular architecture and assembly of the DDB1-CUL4A ubiquitin ligase machinery
    Angers, Stephane
    Li, Ti
    Yi, Xianhua
    MacCoss, Michael J.
    Moon, Randall T.
    Zheng, Ning
    [J]. NATURE, 2006, 443 (7111) : 590 - 593
  • [3] [Anonymous], 2009, ANGEW CHEM-GER EDIT
  • [4] Lenalidomide in the treatment of multiple myeloma: a review
    Armoiry, X.
    Aulagner, G.
    Facon, T.
    [J]. JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS, 2008, 33 (03) : 219 - 226
  • [5] p63 is a cereblon substrate involved in thalidomide teratogenicity
    Asatsuma-Okumura, Tomoko
    Ando, Hideki
    De Simone, Marco
    Yamamoto, Junichi
    Sato, Tomomi
    Shimizu, Nobuyuki
    Asakawa, Kazuhide
    Yamaguchi, Yuki
    Ito, Takumi
    Guerrini, Luisa
    Handa, Hiroshi
    [J]. NATURE CHEMICAL BIOLOGY, 2019, 15 (11) : 1077 - +
  • [6] Pd-PEPPSI-IHeptCl: A General-Purpose, Highly Reactive Catalyst for the Selective Coupling of Secondary Alkyl Organozincs
    Atwater, Bruce
    Chandrasoma, Nalin
    Mitchell, David
    Rodriguez, Michael J.
    Organ, Michael G.
    [J]. CHEMISTRY-A EUROPEAN JOURNAL, 2016, 22 (41) : 14531 - 14534
  • [7] Bondeson DP, 2015, NAT CHEM BIOL, V11, P611, DOI [10.1038/NCHEMBIO.1858, 10.1038/nchembio.1858]
  • [8] [Pd(IPr*)(3-Cl-pyridinyl)Cl2]: A Novel and Efficient PEPPSI Precatalyst
    Chartoire, Anthony
    Frogneux, Xavier
    Boreux, Arnaud
    Slawin, Alexandra M. Z.
    Nolan, Steven P.
    [J]. ORGANOMETALLICS, 2012, 31 (19) : 6947 - 6951
  • [9] Crews C.M., 2018, Patent No. [2018119448 A1, 2018119448]
  • [10] Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome
    Donovan, Katherine A.
    An, Jian
    Nowak, Radoslaw P.
    Yuan, Jingting C.
    Fink, Emma C.
    Berry, Bethany C.
    Ebert, Benjamin L.
    Fischer, Eric S.
    [J]. ELIFE, 2018, 7
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