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

Svenja Lier; Andreas Sellmer; Felix Orben; Stephanie Heinzlmeir; Lukas Krauß; Christian Schneeweis; Zonera Hassan; Carolin Schneider; Arlett Patricia Gloria Schäfer; Herwig Pongratz; Thomas Engleitner; Rupert Öllinger; Anna Kuisl; Florian Bassermann; Christoph Schlag; Bo Kong; Stefan Dove; Bernhard Kuster; Roland Rad; Maximilian Reichert; Matthias Wirth; Dieter Saur; Siavosh Mahboobi; Günter Schneider

doi:10.1016/j.bioorg.2021.105505

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

Svenja Lier, Andreas Sellmer, Felix Orben, Stephanie Heinzlmeir, Lukas Krauß, Christian Schneeweis, Zonera Hassan, Carolin Schneider, Arlett Patricia Gloria Schäfer, Herwig Pongratz, Thomas Engleitner, Rupert Öllinger, Anna Kuisl, Florian Bassermann, Christoph Schlag, Bo Kong, Stefan Dove, Bernhard Kuster, Roland Rad, Maximilian ReichertMatthias Wirth, Dieter Saur, Siavosh Mahboobi, Günter Schneider

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

Abstract

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 gastrointestinal cancer cell lines and primary patient-derived organoids are MDEG-541 sensitive. Although MYC expression was regulated in a CRBN-, proteasome- and ubiquitin-dependent manner, we provide evidence that MDEG-541 induced the degradation of CRBN neosubstrates, including G1 to S phase transition 1/2 (GSPT1/2) and the Polo-like kinase 1 (PLK1). In sum, we have established a CRBN-dependent degrader of relevant cancer targets with activity in gastrointestinal cancers.

Original language	English
Article number	105505
Journal	Bioorganic Chemistry
Volume	119
DOIs	https://doi.org/10.1016/j.bioorg.2021.105505
State	Published - Feb 2022

Keywords

Cereblon
GSPT1
GSPT2
MYC
PLK1

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Lier, S., Sellmer, A., Orben, F., Heinzlmeir, S., Krauß, L., Schneeweis, C., Hassan, Z., Schneider, C., Patricia Gloria Schäfer, A., Pongratz, H., Engleitner, T., Öllinger, R., Kuisl, A., Bassermann, F., Schlag, C., Kong, B., Dove, S., Kuster, B., Rad, R., ... Schneider, G. (2022). A novel Cereblon E3 ligase modulator with antitumor activity in gastrointestinal cancer. Bioorganic Chemistry, 119, Article 105505. https://doi.org/10.1016/j.bioorg.2021.105505

@article{2b49e7881a9d42e08a821fe461229b8f,

title = "A novel Cereblon E3 ligase modulator with antitumor activity in gastrointestinal cancer",

abstract = "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 gastrointestinal cancer cell lines and primary patient-derived organoids are MDEG-541 sensitive. Although MYC expression was regulated in a CRBN-, proteasome- and ubiquitin-dependent manner, we provide evidence that MDEG-541 induced the degradation of CRBN neosubstrates, including G1 to S phase transition 1/2 (GSPT1/2) and the Polo-like kinase 1 (PLK1). In sum, we have established a CRBN-dependent degrader of relevant cancer targets with activity in gastrointestinal cancers.",

keywords = "Cereblon, GSPT1, GSPT2, MYC, PLK1",

author = "Svenja Lier and Andreas Sellmer and Felix Orben and Stephanie Heinzlmeir and Lukas Krau{\ss} and Christian Schneeweis and Zonera Hassan and Carolin Schneider and {Patricia Gloria Sch{\"a}fer}, Arlett and Herwig Pongratz and Thomas Engleitner and Rupert {\"O}llinger and Anna Kuisl and Florian Bassermann and Christoph Schlag and Bo Kong and Stefan Dove and Bernhard Kuster and Roland Rad and Maximilian Reichert and Matthias Wirth and Dieter Saur and Siavosh Mahboobi and G{\"u}nter Schneider",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2022",

month = feb,

doi = "10.1016/j.bioorg.2021.105505",

language = "English",

volume = "119",

journal = "Bioorganic Chemistry",

issn = "0045-2068",

publisher = "Academic Press Inc.",

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Lier, S, Sellmer, A, Orben, F, Heinzlmeir, S, Krauß, L, Schneeweis, C, Hassan, Z, Schneider, C, Patricia Gloria Schäfer, A, Pongratz, H, Engleitner, T, Öllinger, R, Kuisl, A, Bassermann, F, Schlag, C, Kong, B, Dove, S, Kuster, B , Rad, R , Reichert, M, Wirth, M, Saur, D, Mahboobi, S & Schneider, G 2022, 'A novel Cereblon E3 ligase modulator with antitumor activity in gastrointestinal cancer', Bioorganic Chemistry, vol. 119, 105505. https://doi.org/10.1016/j.bioorg.2021.105505

TY - JOUR

T1 - A novel Cereblon E3 ligase modulator with antitumor activity in gastrointestinal cancer

AU - Lier, Svenja

AU - Sellmer, Andreas

AU - Orben, Felix

AU - Heinzlmeir, Stephanie

AU - Krauß, Lukas

AU - Schneeweis, Christian

AU - Hassan, Zonera

AU - Schneider, Carolin

AU - Patricia Gloria Schäfer, Arlett

AU - Pongratz, Herwig

AU - Engleitner, Thomas

AU - Öllinger, Rupert

AU - Kuisl, Anna

AU - Bassermann, Florian

AU - Schlag, Christoph

AU - Kong, Bo

AU - Dove, Stefan

AU - Kuster, Bernhard

AU - Rad, Roland

AU - Reichert, Maximilian

AU - Wirth, Matthias

AU - Saur, Dieter

AU - Mahboobi, Siavosh

AU - Schneider, Günter

PY - 2022/2

Y1 - 2022/2

N2 - 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 gastrointestinal cancer cell lines and primary patient-derived organoids are MDEG-541 sensitive. Although MYC expression was regulated in a CRBN-, proteasome- and ubiquitin-dependent manner, we provide evidence that MDEG-541 induced the degradation of CRBN neosubstrates, including G1 to S phase transition 1/2 (GSPT1/2) and the Polo-like kinase 1 (PLK1). In sum, we have established a CRBN-dependent degrader of relevant cancer targets with activity in gastrointestinal cancers.

AB - 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 gastrointestinal cancer cell lines and primary patient-derived organoids are MDEG-541 sensitive. Although MYC expression was regulated in a CRBN-, proteasome- and ubiquitin-dependent manner, we provide evidence that MDEG-541 induced the degradation of CRBN neosubstrates, including G1 to S phase transition 1/2 (GSPT1/2) and the Polo-like kinase 1 (PLK1). In sum, we have established a CRBN-dependent degrader of relevant cancer targets with activity in gastrointestinal cancers.

KW - Cereblon

KW - GSPT1

KW - GSPT2

KW - MYC

KW - PLK1

UR - http://www.scopus.com/inward/record.url?scp=85119920036&partnerID=8YFLogxK

U2 - 10.1016/j.bioorg.2021.105505

DO - 10.1016/j.bioorg.2021.105505

M3 - Article

C2 - 34838332

AN - SCOPUS:85119920036

SN - 0045-2068

VL - 119

JO - Bioorganic Chemistry

JF - Bioorganic Chemistry

M1 - 105505

ER -

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

Abstract

Keywords

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