2. Academic Validation
  3. Anti-tumor efficacy of a novel CLK inhibitor via targeting RNA splicing and MYC-dependent vulnerability

Anti-tumor efficacy of a novel CLK inhibitor via targeting RNA splicing and MYC-dependent vulnerability

  • EMBO Mol Med. 2018 Jun;10(6):e8289. doi: 10.15252/emmm.201708289.
Kenichi Iwai 1,  Masahiro Yaguchi 1,  Kazuho Nishimura 1,  Yukiko Yamamoto 1,  Toshiya Tamura 1,  Daisuke Nakata 1,  Ryo Dairiki 1,  Yoichi Kawakita 1,  Ryo Mizojiri 1,  Yoshiteru Ito 1,  Moriteru Asano 1,  Hironobu Maezaki 1,  Yusuke Nakayama 2,  Misato Kaishima 2,  Kozo Hayashi 2,  Mika Teratani 2,  Shuichi Miyakawa 3,  Misa Iwatani 3,  Maki Miyamoto 4,  Michael G Klein 5,  Wes Lane 5,  Gyorgy Snell 5,  Richard Tjhen 5,  Xingyue He 6,  Sai Pulukuri 6,  Toshiyuki Nomura 7
Affiliations

Affiliations

  • 1 Oncology Drug Discovery Unit, Takeda Pharmaceutical Company, Limited, Fujisawa, Japan.
  • 2 Integrated Technology Research Laboratories, Takeda Pharmaceutical Company, Limited, Fujisawa, Japan.
  • 3 Biomolecular Research Laboratories, Takeda Pharmaceutical Company, Limited, Fujisawa, Japan.
  • 4 Drug Metabolism & Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company, Limited, Fujisawa, Japan.
  • 5 Department of Structural Biology, Takeda California Inc., San Diego, CA, USA.
  • 6 Oncology Drug Discovery Unit, Takeda Pharmaceuticals International Co., Cambridge, MA, USA.
  • 7 Oncology Drug Discovery Unit, Takeda Pharmaceutical Company, Limited, Fujisawa, Japan toshiyuki.nomura@takeda.com.
PMID: 29769258 DOI: 10.15252/emmm.201708289
Abstract

The modulation of pre-mRNA splicing is proposed as an attractive anti-neoplastic strategy, especially for the cancers that exhibit aberrant pre-mRNA splicing. Here, we discovered that T-025 functions as an orally available and potent inhibitor of Cdc2-like kinases (CLKs), evolutionally conserved kinases that facilitate exon recognition in the splicing machinery. Treatment with T-025 reduced CLK-dependent phosphorylation, resulting in the induction of skipped exons, cell death, and growth suppression in vitro and in vivo Further, through growth inhibitory characterization, we identified high CLK2 expression or MYC amplification as a sensitive-associated biomarker of T-025. Mechanistically, the level of CLK2 expression correlated with the magnitude of global skipped exons in response to T-025 treatment. MYC activation, which altered pre-mRNA splicing without the transcriptional regulation of CLKs, rendered Cancer cells vulnerable to CLK inhibitors with synergistic cell death. Finally, we demonstrated in vivo anti-tumor efficacy of T-025 in an allograft model of spontaneous, MYC-driven breast Cancer, at well-tolerated dosage. Collectively, our results suggest that the novel CLK Inhibitor could have therapeutic benefits, especially for MYC-driven Cancer patients.

Keywords

MYC; CLK2; Cdc2‐like kinase inhibitor; alternative splicing.

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