2. Academic Validation
  3. Quinazolinone-Based Anticancer Agents: Synthesis, Antiproliferative SAR, Antitubulin Activity, and Tubulin Co-crystal Structure

Quinazolinone-Based Anticancer Agents: Synthesis, Antiproliferative SAR, Antitubulin Activity, and Tubulin Co-crystal Structure

  • J Med Chem. 2018 Feb 8;61(3):1031-1044. doi: 10.1021/acs.jmedchem.7b01474.
Wolfgang Dohle 1,  Fabrice L Jourdan 2,  Grégory Menchon 3,  Andrea E Prota 3,  Paul A Foster 4 5,  Pascoe Mannion 4 5,  Ernest Hamel 6,  Mark P Thomas 2,  Philip G Kasprzyk 7,  Eric Ferrandis 8,  Michel O Steinmetz 3 9,  Mathew P Leese 2,  Barry V L Potter 1 2
Affiliations

Affiliations

  • 1 Medicinal Chemistry & Drug Discovery, Department of Pharmacology, University of Oxford , Mansfield Road, Oxford OX1 3QT, U.K.
  • 2 Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath , Claverton Down, Bath BA2 7AY, U.K.
  • 3 Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institut , 5232 Villigen PSI, Switzerland.
  • 4 Institute of Metabolism and Systems Research, University of Birmingham , 2nd Floor IBR Tower, Birmingham B15 2TT, U.K.
  • 5 Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners , Birmingham B15 2TH, U.K.
  • 6 Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute , Frederick, Maryland 21702, United States.
  • 7 IPSEN , 27 Maple Street, Milford Massachusetts 01757, United States.
  • 8 Institut de Recherche Henri Beaufour, IPSEN , 91966 Les Ulis Cedex, France.
  • 9 University of Basel, Biozentrum , 4056 Basel, Switzerland.
PMID: 29227648 DOI: 10.1021/acs.jmedchem.7b01474
Abstract

Quinazolinone-based Anticancer agents were designed, decorated with functional groups from a 2-methoxyestradiol-based microtubule disruptor series, incorporating the aryl sulfamate motif of Steroid Sulfatase (STS) inhibitors. The steroidal AB-ring system was mimicked, favoring conformations with an N-2 substituent occupying D-ring space. Evaluation against breast and prostate tumor cell lines identified 7b with DU-145 antiproliferative activity (GI50 300 nM). A preliminary structure-activity relationship afforded compounds (e.g., 7j GI50 50 nM) with activity exceeding that of the parent. Both 7b and 7j inhibit tubulin assembly in vitro and colchicine binding, and 7j was successfully co-crystallized with the αβ-tubulin heterodimer as the first of its class, its sulfamate group interacting positively at the colchicine binding site. Microtubule destabilization by 7j is likely achieved by preventing the curved-to-straight conformational transition in αβ-tubulin. Quinazolinone sulfamates surprisingly showed weak STS inhibition. Preliminary in vivo studies in a multiple myeloma xenograft model for 7b showed oral activity, confirming the promise of this template.

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