Catalytic Degraders Effectively Address Kinase Site Mutations in EML4-ALK Oncogenic Fusions
Heterobifunctional degraders, known as proteolysis targeting chimeras (PROTACs), theoretically possess a catalytic mode-of-action, yet few studies have either confirmed or exploited this potential advantage of event-driven pharmacology. Degraders of oncogenic EML4-ALK fusions were developed by conju...
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| Veröffentlicht in: | Journal of medicinal chemistry Jg. 66; H. 8; S. 5524 |
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27.04.2023
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| Abstract | Heterobifunctional degraders, known as proteolysis targeting chimeras (PROTACs), theoretically possess a catalytic mode-of-action, yet few studies have either confirmed or exploited this potential advantage of event-driven pharmacology. Degraders of oncogenic EML4-ALK fusions were developed by conjugating ALK inhibitors to cereblon ligands. Simultaneous optimization of pharmacology and compound properties using ternary complex modeling and physicochemical considerations yielded multiple catalytic degraders that were more resilient to clinically relevant ATP-binding site mutations than kinase inhibitor drugs. Our strategy culminated in the design of the orally bioavailable derivative CPD-1224 that avoided hemolysis (a feature of detergent-like PROTACs), degraded the otherwise recalcitrant mutant L1196M/G1202R in vivo, and commensurately slowed tumor growth, while the third generation ALK inhibitor drug lorlatinib had no effect. These results validate our original therapeutic hypothesis by exemplifying opportunities for catalytic degraders to proactively address binding site resistant mutations in cancer. |
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| AbstractList | Heterobifunctional degraders, known as proteolysis targeting chimeras (PROTACs), theoretically possess a catalytic mode-of-action, yet few studies have either confirmed or exploited this potential advantage of event-driven pharmacology. Degraders of oncogenic EML4-ALK fusions were developed by conjugating ALK inhibitors to cereblon ligands. Simultaneous optimization of pharmacology and compound properties using ternary complex modeling and physicochemical considerations yielded multiple catalytic degraders that were more resilient to clinically relevant ATP-binding site mutations than kinase inhibitor drugs. Our strategy culminated in the design of the orally bioavailable derivative CPD-1224 that avoided hemolysis (a feature of detergent-like PROTACs), degraded the otherwise recalcitrant mutant L1196M/G1202R in vivo, and commensurately slowed tumor growth, while the third generation ALK inhibitor drug lorlatinib had no effect. These results validate our original therapeutic hypothesis by exemplifying opportunities for catalytic degraders to proactively address binding site resistant mutations in cancer.Heterobifunctional degraders, known as proteolysis targeting chimeras (PROTACs), theoretically possess a catalytic mode-of-action, yet few studies have either confirmed or exploited this potential advantage of event-driven pharmacology. Degraders of oncogenic EML4-ALK fusions were developed by conjugating ALK inhibitors to cereblon ligands. Simultaneous optimization of pharmacology and compound properties using ternary complex modeling and physicochemical considerations yielded multiple catalytic degraders that were more resilient to clinically relevant ATP-binding site mutations than kinase inhibitor drugs. Our strategy culminated in the design of the orally bioavailable derivative CPD-1224 that avoided hemolysis (a feature of detergent-like PROTACs), degraded the otherwise recalcitrant mutant L1196M/G1202R in vivo, and commensurately slowed tumor growth, while the third generation ALK inhibitor drug lorlatinib had no effect. These results validate our original therapeutic hypothesis by exemplifying opportunities for catalytic degraders to proactively address binding site resistant mutations in cancer. Heterobifunctional degraders, known as proteolysis targeting chimeras (PROTACs), theoretically possess a catalytic mode-of-action, yet few studies have either confirmed or exploited this potential advantage of event-driven pharmacology. Degraders of oncogenic EML4-ALK fusions were developed by conjugating ALK inhibitors to cereblon ligands. Simultaneous optimization of pharmacology and compound properties using ternary complex modeling and physicochemical considerations yielded multiple catalytic degraders that were more resilient to clinically relevant ATP-binding site mutations than kinase inhibitor drugs. Our strategy culminated in the design of the orally bioavailable derivative CPD-1224 that avoided hemolysis (a feature of detergent-like PROTACs), degraded the otherwise recalcitrant mutant L1196M/G1202R in vivo, and commensurately slowed tumor growth, while the third generation ALK inhibitor drug lorlatinib had no effect. These results validate our original therapeutic hypothesis by exemplifying opportunities for catalytic degraders to proactively address binding site resistant mutations in cancer. |
| Author | Hatcher, John M Liu, Yingpeng Fischer, Eric S Liuni, Peter P Gao, Yang Gray, Nathanael S Metivier, Rebecca J Huerta, Fidel Nowak, Radosław P Jones, Lyn H Kim, Hellen Murali, Vineeth K Che, Jianwei Berberich, Matthew J Donovan, Katherine A Zhang, Tinghu Kwiatkowski, Nicholas P Jiang, Baishan |
| Author_xml | – sequence: 1 givenname: Yang surname: Gao fullname: Gao, Yang organization: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States – sequence: 2 givenname: Baishan orcidid: 0000-0001-6796-9500 surname: Jiang fullname: Jiang, Baishan organization: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States – sequence: 3 givenname: Hellen surname: Kim fullname: Kim, Hellen organization: Center for Protein Degradation, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States – sequence: 4 givenname: Matthew J orcidid: 0000-0003-2196-3757 surname: Berberich fullname: Berberich, Matthew J organization: Center for Protein Degradation, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States – sequence: 5 givenname: Jianwei surname: Che fullname: Che, Jianwei organization: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States – sequence: 6 givenname: Katherine A orcidid: 0000-0002-8539-5106 surname: Donovan fullname: Donovan, Katherine A organization: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States – sequence: 7 givenname: John M surname: Hatcher fullname: Hatcher, John M organization: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States – sequence: 8 givenname: Fidel surname: Huerta fullname: Huerta, Fidel organization: Center for Protein Degradation, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States – sequence: 9 givenname: Nicholas P surname: Kwiatkowski fullname: Kwiatkowski, Nicholas P organization: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States – sequence: 10 givenname: Yingpeng orcidid: 0000-0002-2752-2947 surname: Liu fullname: Liu, Yingpeng organization: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States – sequence: 11 givenname: Peter P surname: Liuni fullname: Liuni, Peter P organization: Center for Protein Degradation, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States – sequence: 12 givenname: Rebecca J orcidid: 0000-0001-9929-6857 surname: Metivier fullname: Metivier, Rebecca J organization: Center for Protein Degradation, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States – sequence: 13 givenname: Vineeth K surname: Murali fullname: Murali, Vineeth K organization: Center for Protein Degradation, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States – sequence: 14 givenname: Radosław P orcidid: 0000-0002-0605-0071 surname: Nowak fullname: Nowak, Radosław P organization: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States – sequence: 15 givenname: Tinghu surname: Zhang fullname: Zhang, Tinghu organization: Department of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, California 94305, United States – sequence: 16 givenname: Eric S orcidid: 0000-0001-7337-6306 surname: Fischer fullname: Fischer, Eric S organization: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States – sequence: 17 givenname: Nathanael S orcidid: 0000-0001-5354-7403 surname: Gray fullname: Gray, Nathanael S organization: Department of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, California 94305, United States – sequence: 18 givenname: Lyn H orcidid: 0000-0002-8388-5865 surname: Jones fullname: Jones, Lyn H organization: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States |
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| SubjectTerms | Anaplastic Lymphoma Kinase Antineoplastic Agents - pharmacology Drug Resistance, Neoplasm Humans Lung Neoplasms - drug therapy Mutation Oncogene Proteins, Fusion - genetics Protein Kinase Inhibitors - pharmacology Receptor Protein-Tyrosine Kinases |
| Title | Catalytic Degraders Effectively Address Kinase Site Mutations in EML4-ALK Oncogenic Fusions |
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