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Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
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Protein Translation Inhibition is Involved in the Activity of the Pan-PIM Kinase Inhibitor PIM447 in Combination with

Teresa Paíno1, Lorena González-Méndez1, Laura San-Segundo1

  • 1Centro de Investigación del Cáncer-IBMCC (CSIC-Universidad de Salamanca), Complejo Asistencial Universitario de Salamanca-IBSAL, 37007 Salamanca, Spain.

Cancers
|September 29, 2020
PubMed
Abstract

Insights

The triple combination of PIM447, pomalidomide, and dexamethasone (PIM-Pd) shows potent anti-myeloma effects. This novel therapy inhibits protein translation and downregulates key survival factors, supporting clinical evaluation for multiple myeloma treatment.

Area of Science:

  • Hematologic Malignancies
  • Cancer Pharmacology
  • Molecular Oncology

Background:

  • Proviral Insertion site for Moloney murine leukemia virus (PIM) kinases are overexpressed in multiple myeloma (MM).
  • Preclinical studies demonstrated the anti-myeloma efficacy of the pan-PIM kinase inhibitor PIM447.

Purpose of the Study:

  • To evaluate the in vitro and in vivo activity of a triple combination therapy (PIM447 + pomalidomide + dexamethasone) in multiple myeloma.
  • To investigate the molecular mechanisms underlying the anti-myeloma effects of the PIM-Pd combination.

Main Methods:

  • In vitro and in vivo studies were conducted to assess the efficacy of the PIM-Pd combination.
  • Mechanism of action studies were performed on in vitro cell models and ex vivo mouse tumor samples.

Main Results:

  • The PIM-Pd combination demonstrated potent anti-myeloma activity, significantly delaying tumor growth and prolonging survival in mice.
  • The combination inhibits protein translation via convergent inhibition of c-Myc and mTORC1, disrupting eIF4E function.
  • Downregulation of the MM pro-survival factor IRF4 was observed, leading to cell cycle arrest and metabolic pathway deregulation.

Conclusions:

  • The PIM-Pd triple combination exhibits significant anti-myeloma effects both in vitro and in vivo.
  • The findings support the clinical investigation of PIM-Pd as a potential treatment for patients with multiple myeloma.
Keywords:
drug combinationmultiple myelomapan-PIM kinase inhibitorprotein translation

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