Structure-Based Optimization of a Series of Covalent, Cell Active Bfl‑1 Inhibitors
Bfl-1, a member of the Bcl-2 family of proteins, plays a crucial role in apoptosis regulation and has been implicated in cancer cell survival and resistance to venetoclax therapy. Due to the unique cysteine residue in the BH3 binding site, the development of covalent inhibitors targeting Bfl-1 repre...
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| Veröffentlicht in: | Journal of medicinal chemistry 2024-09, Vol.67 (18), p.16455-16479 |
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| creator | Lucas, Simon C. C. Blackwell, J. Henry Börjesson, Ulf Hargreaves, David Milbradt, Alexander G. Bostock, Mark J. Ahmed, Samiyah Beaumont, Kevin Cheung, Tony Demanze, Sylvain Gohlke, Andrea Guerot, Carine Haider, Afreen Kantae, Vasudev Kauffman, Gregory W. Kinzel, Olaf Kupcova, Lea Lainchbury, Michael D. Lamb, Michelle L. Leon, Leonardo Palisse, Adeline Sacchetto, Claudia Storer, R. Ian Su, Nancy Thomson, Clare Vales, John Chen, Yunhua Hu, Xiaolong |
| description | Bfl-1, a member of the Bcl-2 family of proteins, plays a crucial role in apoptosis regulation and has been implicated in cancer cell survival and resistance to venetoclax therapy. Due to the unique cysteine residue in the BH3 binding site, the development of covalent inhibitors targeting Bfl-1 represents a promising strategy for cancer treatment. Herein, the optimization of a covalent cellular tool from a lead-like hit using structure based design is described. Informed by a reversible X-ray fragment screen, the strategy to establish interactions with a key glutamic acid residue (Glu78) and optimize binding in a cryptic pocket led to a 1000-fold improvement in biochemical potency without increasing reactivity of the warhead. Compound (R,R,S)-26 has a k inact /K I of 4600 M–1 s–1, shows |
| doi_str_mv | 10.1021/acs.jmedchem.4c01288 |
| format | Article |
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Ian</creatorcontrib><creatorcontrib>Su, Nancy</creatorcontrib><creatorcontrib>Thomson, Clare</creatorcontrib><creatorcontrib>Vales, John</creatorcontrib><creatorcontrib>Chen, Yunhua</creatorcontrib><creatorcontrib>Hu, Xiaolong</creatorcontrib><title>Structure-Based Optimization of a Series of Covalent, Cell Active Bfl‑1 Inhibitors</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Bfl-1, a member of the Bcl-2 family of proteins, plays a crucial role in apoptosis regulation and has been implicated in cancer cell survival and resistance to venetoclax therapy. Due to the unique cysteine residue in the BH3 binding site, the development of covalent inhibitors targeting Bfl-1 represents a promising strategy for cancer treatment. Herein, the optimization of a covalent cellular tool from a lead-like hit using structure based design is described. Informed by a reversible X-ray fragment screen, the strategy to establish interactions with a key glutamic acid residue (Glu78) and optimize binding in a cryptic pocket led to a 1000-fold improvement in biochemical potency without increasing reactivity of the warhead. 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Chem</addtitle><date>2024-09-26</date><risdate>2024</risdate><volume>67</volume><issue>18</issue><spage>16455</spage><epage>16479</epage><pages>16455-16479</pages><issn>0022-2623</issn><issn>1520-4804</issn><eissn>1520-4804</eissn><abstract>Bfl-1, a member of the Bcl-2 family of proteins, plays a crucial role in apoptosis regulation and has been implicated in cancer cell survival and resistance to venetoclax therapy. Due to the unique cysteine residue in the BH3 binding site, the development of covalent inhibitors targeting Bfl-1 represents a promising strategy for cancer treatment. Herein, the optimization of a covalent cellular tool from a lead-like hit using structure based design is described. Informed by a reversible X-ray fragment screen, the strategy to establish interactions with a key glutamic acid residue (Glu78) and optimize binding in a cryptic pocket led to a 1000-fold improvement in biochemical potency without increasing reactivity of the warhead. Compound (R,R,S)-26 has a k inact /K I of 4600 M–1 s–1, shows <1 μM caspase activation in a cellular assay and cellular target engagement, and has good physicochemical properties and a promising in vivo profile.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>39291659</pmid><doi>10.1021/acs.jmedchem.4c01288</doi><tpages>25</tpages><orcidid>https://orcid.org/0000-0002-9172-8739</orcidid><orcidid>https://orcid.org/0000-0003-4533-6280</orcidid><orcidid>https://orcid.org/0000-0001-8944-9565</orcidid><orcidid>https://orcid.org/0000-0003-3160-1397</orcidid><orcidid>https://orcid.org/0000-0002-3005-8065</orcidid><orcidid>https://orcid.org/0000-0001-8541-0882</orcidid></addata></record> |
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| subjects | Animals Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Apoptosis - drug effects Cell Line, Tumor Crystallography, X-Ray Humans Mice Minor Histocompatibility Antigens Models, Molecular Molecular Structure Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors Proto-Oncogene Proteins c-bcl-2 - metabolism Structure-Activity Relationship |
| title | Structure-Based Optimization of a Series of Covalent, Cell Active Bfl‑1 Inhibitors |
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