Design and Development of IKZF2 and CK1α Dual Degraders
Lenalidomide achieves its therapeutic efficacy by recruiting and removing proteins of therapeutic interest through the E3 ligase substrate adapter cereblon. Here, we report the design and characterization of 81 cereblon ligands for their ability to degrade the transcription factor Helios (IKZF2) and casein kinase 1 alpha (CK1α). We identified a key naphthamide scaffold that depleted both intended targets in acute myeloid leukemia MOLM-13 cells. Structure-activity relationship studies for degradation of the desired targets over other targets (IKZF1, GSPT1) afforded an initial lead compound DEG-35. A subsequent scaffold replacement campaign identified DEG-77, which selectively degrades IKZF2 and CK1α, and possesses suitable pharmacokinetic properties, solubility, and selectivity for in vivo studies. Finally, we show that DEG-77 has antiproliferative activity in the diffuse large B cell lymphoma cell line OCI-LY3 and the ovarian cancer cell line A2780 indicating that the dual degrader strategy may have efficacy against additional types of cancer.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:66 |
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| Enthalten in: |
Journal of medicinal chemistry - 66(2023), 24 vom: 28. Dez., Seite 16953-16979 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Miyamoto, David K [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 29.12.2023 Date Revised 01.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jmedchem.3c01736 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM365763640 |
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| 100 | 1 | |a Miyamoto, David K |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Design and Development of IKZF2 and CK1α Dual Degraders |
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| 500 | |a Date Completed 29.12.2023 | ||
| 500 | |a Date Revised 01.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Lenalidomide achieves its therapeutic efficacy by recruiting and removing proteins of therapeutic interest through the E3 ligase substrate adapter cereblon. Here, we report the design and characterization of 81 cereblon ligands for their ability to degrade the transcription factor Helios (IKZF2) and casein kinase 1 alpha (CK1α). We identified a key naphthamide scaffold that depleted both intended targets in acute myeloid leukemia MOLM-13 cells. Structure-activity relationship studies for degradation of the desired targets over other targets (IKZF1, GSPT1) afforded an initial lead compound DEG-35. A subsequent scaffold replacement campaign identified DEG-77, which selectively degrades IKZF2 and CK1α, and possesses suitable pharmacokinetic properties, solubility, and selectivity for in vivo studies. Finally, we show that DEG-77 has antiproliferative activity in the diffuse large B cell lymphoma cell line OCI-LY3 and the ovarian cancer cell line A2780 indicating that the dual degrader strategy may have efficacy against additional types of cancer | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Lenalidomide |2 NLM | |
| 650 | 7 | |a F0P408N6V4 |2 NLM | |
| 650 | 7 | |a Ubiquitin-Protein Ligases |2 NLM | |
| 650 | 7 | |a EC 2.3.2.27 |2 NLM | |
| 650 | 7 | |a Casein Kinase Ialpha |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a IKZF2 protein, human |2 NLM | |
| 650 | 7 | |a Ikaros Transcription Factor |2 NLM | |
| 650 | 7 | |a 148971-36-2 |2 NLM | |
| 700 | 1 | |a Curnutt, Nicole M |e verfasserin |4 aut | |
| 700 | 1 | |a Park, Sun-Mi |e verfasserin |4 aut | |
| 700 | 1 | |a Stavropoulos, Alexios |e verfasserin |4 aut | |
| 700 | 1 | |a Kharas, Michael G |e verfasserin |4 aut | |
| 700 | 1 | |a Woo, Christina M |e verfasserin |4 aut | |
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