A phenylphthalimide derivative, TC11, induces apoptosis by degrading MCL1 in multiple myeloma cells

Daiju Ichikawa, Misa Nakamura, Wakana Murota, Sho Osawa, Maiko Matsushita, Hiroshi Yanagawa, Yutaka Hattori

Research output: Contribution to journalArticle

Abstract

To date, the prognosis of multiple myeloma (MM) in patients harboring cytogenetic abnormalities (CA) involving t (4; 14) and deletion of chromosome 17 remains poor despite recent advances in drug development that include the use of immunomodulatory drugs (IMiDs) such as lenalidomide for MM. To address this issue, we have developed a novel phenylphthalimide derivative, TC11, that is structurally related to IMiDs. It remains unclear how TC11 induces apoptosis of MM cells with high-risk CA. Here, we show that TC11 does not induce degradation of CRBN's substrates, IKZF1/3 and CK1α, and induces apoptosis of CRBN-silenced MM; this effect was independent of the cereblon (CRBN) pathway, which is involved in the mechanism of action of IMiDs used for the treatment of MM. We also revealed that TC11, in contrast to existing IMiDs, induced degradation of MCL1 and activation of caspase-9. Furthermore, inhibition of CDK1 by CGP74514A prevented TC11-induced MCL1 degradation, caspase-9 activation, and the subsequent apoptotic cell death. We showed that ectopic MCL1 expression rescued apoptosis of MM. These observations suggest that TC11 induces apoptotic death caused by degradation of MCL1 during prolonged mitotic arrest. Therefore, our findings suggest that TC11 is a potential drug candidate for high-risk MM.

Original languageEnglish
JournalBiochemical and Biophysical Research Communications
DOIs
Publication statusAccepted/In press - 2019 Jan 1

Fingerprint

Multiple Myeloma
Apoptosis
Derivatives
Degradation
Caspase 9
Chemical activation
Pharmaceutical Preparations
Chromosome Aberrations
Cell death
Chromosomes
Substrates
Cell Death

Keywords

  • Cyclin-dependent kinase 1 (CDK1)
  • MCL1
  • Multiple myeloma
  • TC11

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

A phenylphthalimide derivative, TC11, induces apoptosis by degrading MCL1 in multiple myeloma cells. / Ichikawa, Daiju; Nakamura, Misa; Murota, Wakana; Osawa, Sho; Matsushita, Maiko; Yanagawa, Hiroshi; Hattori, Yutaka.

In: Biochemical and Biophysical Research Communications, 01.01.2019.

Research output: Contribution to journalArticle

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AU - Ichikawa, Daiju

AU - Nakamura, Misa

AU - Murota, Wakana

AU - Osawa, Sho

AU - Matsushita, Maiko

AU - Yanagawa, Hiroshi

AU - Hattori, Yutaka

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