2. Academic Validation
  3. MELK-T1, a small-molecule inhibitor of protein kinase MELK, decreases DNA-damage tolerance in proliferating cancer cells

MELK-T1, a small-molecule inhibitor of protein kinase MELK, decreases DNA-damage tolerance in proliferating cancer cells

  • Biosci Rep. 2015 Oct 2;35(6):e00267. doi: 10.1042/BSR20150194.
Lijs Beke 1,  Cenk Kig 2,  Joannes T M Linders 1,  Shannah Boens 2,  An Boeckx 1,  Erika van Heerde 1,  Marc Parade 1,  An De Bondt 3,  Ilse Van den Wyngaert 3,  Tarig Bashir 1,  Souichi Ogata 1,  Lieven Meerpoel 1,  Aleyde Van Eynde 2,  Christopher N Johnson 4,  Monique Beullens 5,  Dirk Brehmer 6,  Mathieu Bollen 5
Affiliations

Affiliations

  • 1 Oncology Discovery, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
  • 2 Laboratory of Biosignaling & Therapeutics, KULeuven Department of Cellular and Molecular Medicine, University of Leuven, Campus Gasthuisberg, O&N1/ Box 901, Herestraat 49, 3000 Leuven, Belgium.
  • 3 Computational Sciences, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
  • 4 Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
  • 5 Laboratory of Biosignaling & Therapeutics, KULeuven Department of Cellular and Molecular Medicine, University of Leuven, Campus Gasthuisberg, O&N1/ Box 901, Herestraat 49, 3000 Leuven, Belgium Monique.Beullems@med.kuleuven.be Mathieu.Bollen@med.kuleuven.be dbrehmer@its.jnj.com.
  • 6 Oncology Discovery, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium Monique.Beullems@med.kuleuven.be Mathieu.Bollen@med.kuleuven.be dbrehmer@its.jnj.com.
PMID: 26431963 DOI: 10.1042/BSR20150194
Abstract

Maternal embryonic leucine zipper kinase (MELK), a serine/threonine protein kinase, has oncogenic properties and is overexpressed in many Cancer cells. The oncogenic function of MELK is attributed to its capacity to disable critical cell-cycle checkpoints and reduce replication stress. Most functional studies have relied on the use of siRNA/shRNA-mediated gene silencing. In the present study, we have explored the biological function of MELK using MELK-T1, a novel and selective small-molecule inhibitor. Strikingly, MELK-T1 triggered a rapid and proteasome-dependent degradation of the MELK protein. Treatment of MCF-7 (Michigan Cancer Foundation-7) breast adenocarcinoma cells with MELK-T1 induced the accumulation of stalled replication forks and double-strand breaks that culminated in a replicative senescence phenotype. This phenotype correlated with a rapid and long-lasting ataxia telangiectasia-mutated (ATM) activation and phosphorylation of checkpoint kinase 2 (Chk2). Furthermore, MELK-T1 induced a strong phosphorylation of p53 (cellular tumour antigen p53), a prolonged up-regulation of p21 (cyclin-dependent kinase inhibitor 1) and a down-regulation of FOXM1 (Forkhead Box M1) target genes. Our data indicate that MELK is a key stimulator of proliferation by its ability to increase the threshold for DNA-damage tolerance (DDT). Thus, targeting MELK by the inhibition of both its catalytic activity and its protein stability might sensitize tumours to DNA-damaging agents or radiation therapy by lowering the DNA-damage threshold.

Keywords

chemical biology; deoxyribonucleic acid (DNA) damage response; maternal embryonic leucine zipper kinase (MELK) kinase; senescence; small molecule inhibitors.

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