Design, Synthesis, and Characterization of 4-Aminoquinazolines as Potent Inhibitors of the G Protein-Coupled Receptor Kinase 6 (GRK6) for the Treatment of Multiple Myeloma

  • J Med Chem. 2021 Aug 12;64(15):11129-11147. doi: 10.1021/acs.jmedchem.1c00506.
David E Uehling  1 ,  Babu Joseph  1 ,  Kim Chan Chung  2 ,  Andrew X Zhang  1 ,  Spencer Ler  1 ,  Michael A Prakesch  1 ,  Gennady Poda  1  3 ,  Julie Grouleff  1 ,  Ahmed Aman  1  3 ,  Taira Kiyota  1 ,  Chungyee Leung-Hagesteijn  2 ,  John David Konda  2 ,  Richard Marcellus  1 ,  Carly Griffin  1 ,  Ratheesh Subramaniam  1 ,  Ayome Abibi  1 ,  Craig A Strathdee  1 ,  Methvin B Isaac  1 ,  Rima Al-Awar  1  4 ,  Rodger E Tiedemann  2
Affiliations
  • 1. Drug Discovery Program, Ontario Institute for Cancer Research, MaRS Centre, 661 University Avenue, Suite 510, Toronto, Ontario M5G 0A3, Canada.
  • 2. Princess Margaret Cancer Centre, Toronto Medical Discovery Tower, 101 College Street, Room 12-306, Toronto, Ontario M5G 1L7, Canada.
  • 3. Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario M5S 3M2, Canada.
  • 4. Department of Pharmacology and Toxicology, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
PMID: 34291633 DOI: 10.1021/acs.jmedchem.1c00506
Abstract

Both previous and additional genetic knockdown studies reported herein implicate G protein-coupled receptor kinase 6 (GRK6) as a critical kinase required for the survival of multiple myeloma (MM) cells. Therefore, we sought to develop a small molecule GRK6 inhibitor as an MM therapeutic. From a focused library of known kinase inhibitors, we identified two hits with moderate biochemical potencies against GRK6. From these hits, we developed potent (IC50 < 10 nM) analogues with selectivity against off-target kinases. Further optimization led to the discovery of an analogue (18) with an IC50 value of 6 nM against GRK6 and selectivity against a panel of 85 kinases. Compound 18 has potent cellular target engagement and antiproliferative activity against MM cells and is synergistic with bortezomib. In summary, we demonstrate that targeting GRK6 with small molecule inhibitors represents a promising approach for MM and identify 18 as a novel, potent, and selective GRK6 inhibitor.

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