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PROTAC-triggered degradation of MYC

ABSTRACT: The oncogene MYC drives many cancers and is an outstanding therapeutic target. MYC is an intrinsically disordered protein, and therefore, targeting MYC remains a challenge. Here, we developed a proteolysis targeting chimera (PROTAC) degrading MYC: MDEG-541. The inhibitor is based on the MYC-MAX dimerization inhibitor 10058-F4 and Thalidomide. Mode of action depends on the proteasome and cereblon. MDEG-541 shows single digit mM activity in most sensitive colon and pancreatic cancer cell lines as well as gastrointestinal tumor organoids.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Pancreatic Cancer

SUBMITTER: Stephanie Wilhelm

LAB HEAD: Prof. Dr. Bernhard Kuster

PROVIDER: PXD018674 | Pride | 2022-05-12

REPOSITORIES: Pride

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A novel Cereblon E3 ligase modulator with antitumor activity in gastrointestinal cancer.

Lier Svenja S Sellmer Andreas A Orben Felix F Heinzlmeir Stephanie S Krauß Lukas L Schneeweis Christian C Hassan Zonera Z Schneider Carolin C Patricia Gloria Schäfer Arlett A Pongratz Herwig H Engleitner Thomas T Öllinger Rupert R Kuisl Anna A Bassermann Florian F Schlag Christoph C Kong Bo B Dove Stefan S Kuster Bernhard B Rad Roland R Reichert Maximilian M Wirth Matthias M Saur Dieter D Mahboobi Siavosh S Schneider Günter G

Bioorganic chemistry 20211120

Targeted protein degradation offers new opportunities to inactivate cancer drivers and has successfully entered the clinic. Ways to induce selective protein degradation include proteolysis targeting chimera (PROTAC) technology and immunomodulatory (IMiDs) / next-generation Cereblon (CRBN) E3 ligase modulating drugs (CELMoDs). Here, we aimed to develop a MYC PROTAC based on the MYC-MAX dimerization inhibitor 10058-F4 derivative 28RH and Thalidomide, called MDEG-541. We show that a subgroup of gas ...[more]

PMID: 34838332

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