Cargando…
Controlling Ibrutinib’s Conformations about Its Heterobiaryl Axis to Increase BTK Selectivity
[Image: see text] Ibrutinib is a covalent BTK inhibitor that is approved for several indications in oncology. Ibrutinib possesses significant off-target activities toward many kinases, often leading to adverse events in patients. While there have been robust medicinal chemistry efforts leading to mo...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2023
|
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10009787/ https://www.ncbi.nlm.nih.gov/pubmed/36923918 http://dx.doi.org/10.1021/acsmedchemlett.2c00523 |
_version_ | 1784906058381131776 |
---|---|
author | Toenjes, Sean T. Heydari, Bahar S. Albright, Samuel T. Hazin, Ramsey Ortiz, Maria A. Piedrafita, F. Javier Gustafson, Jeffrey L. |
author_facet | Toenjes, Sean T. Heydari, Bahar S. Albright, Samuel T. Hazin, Ramsey Ortiz, Maria A. Piedrafita, F. Javier Gustafson, Jeffrey L. |
author_sort | Toenjes, Sean T. |
collection | PubMed |
description | [Image: see text] Ibrutinib is a covalent BTK inhibitor that is approved for several indications in oncology. Ibrutinib possesses significant off-target activities toward many kinases, often leading to adverse events in patients. While there have been robust medicinal chemistry efforts leading to more selective second-generation BTK inhibitors, there remains a need for new strategies to rapidly improve the selectivity of kinase inhibitors. An analysis of PDB data revealed that ibrutinib binds BTK in dihedral conformations that are orthogonal of ibrutinib’s predicted low energy conformational range. Synthesis of a series of analogues with ground state conformations shifted toward orthogonality led to the discovery of an analogue with two incorporated ortho-methyl groups that possessed markedly increased BTK selectivity. This work suggests that conformational control about a prospective atropisomeric axis represents a strategy to rapidly program a compound’s selectivity toward a given target. |
format | Online Article Text |
id | pubmed-10009787 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-100097872023-03-14 Controlling Ibrutinib’s Conformations about Its Heterobiaryl Axis to Increase BTK Selectivity Toenjes, Sean T. Heydari, Bahar S. Albright, Samuel T. Hazin, Ramsey Ortiz, Maria A. Piedrafita, F. Javier Gustafson, Jeffrey L. ACS Med Chem Lett [Image: see text] Ibrutinib is a covalent BTK inhibitor that is approved for several indications in oncology. Ibrutinib possesses significant off-target activities toward many kinases, often leading to adverse events in patients. While there have been robust medicinal chemistry efforts leading to more selective second-generation BTK inhibitors, there remains a need for new strategies to rapidly improve the selectivity of kinase inhibitors. An analysis of PDB data revealed that ibrutinib binds BTK in dihedral conformations that are orthogonal of ibrutinib’s predicted low energy conformational range. Synthesis of a series of analogues with ground state conformations shifted toward orthogonality led to the discovery of an analogue with two incorporated ortho-methyl groups that possessed markedly increased BTK selectivity. This work suggests that conformational control about a prospective atropisomeric axis represents a strategy to rapidly program a compound’s selectivity toward a given target. American Chemical Society 2023-02-14 /pmc/articles/PMC10009787/ /pubmed/36923918 http://dx.doi.org/10.1021/acsmedchemlett.2c00523 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Toenjes, Sean T. Heydari, Bahar S. Albright, Samuel T. Hazin, Ramsey Ortiz, Maria A. Piedrafita, F. Javier Gustafson, Jeffrey L. Controlling Ibrutinib’s Conformations about Its Heterobiaryl Axis to Increase BTK Selectivity |
title | Controlling
Ibrutinib’s Conformations about
Its Heterobiaryl Axis to Increase BTK Selectivity |
title_full | Controlling
Ibrutinib’s Conformations about
Its Heterobiaryl Axis to Increase BTK Selectivity |
title_fullStr | Controlling
Ibrutinib’s Conformations about
Its Heterobiaryl Axis to Increase BTK Selectivity |
title_full_unstemmed | Controlling
Ibrutinib’s Conformations about
Its Heterobiaryl Axis to Increase BTK Selectivity |
title_short | Controlling
Ibrutinib’s Conformations about
Its Heterobiaryl Axis to Increase BTK Selectivity |
title_sort | controlling
ibrutinib’s conformations about
its heterobiaryl axis to increase btk selectivity |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10009787/ https://www.ncbi.nlm.nih.gov/pubmed/36923918 http://dx.doi.org/10.1021/acsmedchemlett.2c00523 |
work_keys_str_mv | AT toenjesseant controllingibrutinibsconformationsaboutitsheterobiarylaxistoincreasebtkselectivity AT heydaribahars controllingibrutinibsconformationsaboutitsheterobiarylaxistoincreasebtkselectivity AT albrightsamuelt controllingibrutinibsconformationsaboutitsheterobiarylaxistoincreasebtkselectivity AT hazinramsey controllingibrutinibsconformationsaboutitsheterobiarylaxistoincreasebtkselectivity AT ortizmariaa controllingibrutinibsconformationsaboutitsheterobiarylaxistoincreasebtkselectivity AT piedrafitafjavier controllingibrutinibsconformationsaboutitsheterobiarylaxistoincreasebtkselectivity AT gustafsonjeffreyl controllingibrutinibsconformationsaboutitsheterobiarylaxistoincreasebtkselectivity |