2. Academic Validation
  3. Quinoline and thiazolopyridine allosteric inhibitors of MALT1

Quinoline and thiazolopyridine allosteric inhibitors of MALT1

  • Bioorg Med Chem Lett. 2019 Jul 15;29(14):1694-1698. doi: 10.1016/j.bmcl.2019.05.040.
David A Scott 1,  John M Hatcher 2,  Hongyan Liu 3,  Mingpeng Fu 3,  Guangyan Du 2,  Lorena Fontán 4,  Ilkay Us 4,  Gabriella Casalena 4,  Qi Qiao 5,  Hao Wu 5,  Ari Melnick 4,  Nathanael S Gray 2
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 360 Longwood Ave, Boston, MA 02115, USA. Electronic address: davida_scott@dfci.harvard.edu.
  • 2 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 360 Longwood Ave, Boston, MA 02115, USA.
  • 3 PepTech (Shanghai) Pharmaceutical Corporation, 388 Yindu Road, Shanghai 200231, China.
  • 4 Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA.
  • 5 Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
PMID: 31129051 DOI: 10.1016/j.bmcl.2019.05.040
Abstract

Quinolines and thiazolopyridines were developed as allosteric inhibitors of MALT1, with good cellular potency and exquisite selectivity. Mouse pharmacokinetic (PK) profiling showed these to have low in vivo clearance, and moderate oral exposure. The thiazolopyridines were less lipophilic than the quinolines, and one thiazolopyridine example was active in our hIL10 mouse pharmacodynamic (PD) model upon oral dosing.

Keywords

Allosteric; B-cell lymphomas; MALT1; Protease inhibitors.

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