2. Academic Validation
  3. Discovery and in Vivo Evaluation of Macrocyclic Mcl-1 Inhibitors Featuring an α-Hydroxy Phenylacetic Acid Pharmacophore or Bioisostere

Discovery and in Vivo Evaluation of Macrocyclic Mcl-1 Inhibitors Featuring an α-Hydroxy Phenylacetic Acid Pharmacophore or Bioisostere

  • J Med Chem. 2019 Nov 27;62(22):10258-10271. doi: 10.1021/acs.jmedchem.9b01310.
Gwenaella Rescourio,  Ana Z Gonzalez,  Salman Jabri,  Brian Belmontes,  Gordon Moody,  Doug Whittington,  Xin Huang,  Sean Caenepeel,  Mario Cardozo,  Alan C Cheng,  David Chow,  Hannah Dou,  Adrie Jones,  Ron C Kelly,  Yihong Li,  Mike Lizarzaburu,  Mei-Chu Lo,  Rommel Mallari,  Cesar Meleza,  Yosup Rew,  Scott Simonovich,  Daqing Sun,  Simon Turcotte,  Xuelei Yan,  Simon G Wong,  Evelyn Yanez,  Manuel Zancanella,  Jonathan Houze,  Julio C Medina,  Paul E Hughes,  Sean P Brown
PMID: 31736296 DOI: 10.1021/acs.jmedchem.9b01310
Abstract

Overexpression of the antiapoptotic protein Mcl-1 provides a survival advantage to some Cancer cells, making inhibition of this protein an attractive therapeutic target for the treatment of certain types of tumors. Herein, we report our efforts toward the identification of a novel series of macrocyclic Mcl-1 inhibitors featuring an α-hydroxy phenylacetic acid pharmacophore or bioisostere. This work led to the discovery of 1, a potent Mcl-1 Inhibitor (IC50 = 19 nM in an OPM-2 cell viability assay) with good pharmacokinetic properties and excellent in vivo efficacy in an OPM-2 multiple myeloma xenograft model.

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