File Download
There are no files associated with this item.
Links for fulltext
(May Require Subscription)
- Publisher Website: 10.1073/pnas.2316615121
- Scopus: eid_2-s2.0-85195888081
- PMID: 38861602
- Find via
Supplementary
- Citations:
- Appears in Collections:
Article: Iridium(III) carbene complexes as potent girdin inhibitors against metastatic cancers
Title | Iridium(III) carbene complexes as potent girdin inhibitors against metastatic cancers |
---|---|
Authors | |
Keywords | anticancer compounds Girdin iridium N-heterocyclic carbene |
Issue Date | 11-Jun-2024 |
Publisher | National Academy of Sciences |
Citation | Proceedings of the National Academy of Sciences, 2024, v. 121, n. 25 How to Cite? |
Abstract | Many cancer-driving protein targets remain undruggable due to a lack of binding molecular scaffolds. In this regard, octahedral metal complexes with unique and versatile three-dimensional structures have rarely been explored as inhibitors of undruggable protein targets. Here, we describe antitumor iridium(III) pyridinium-N-heterocyclic carbene complex 1a, which profoundly reduces the viability of lung and breast cancer cells as well as cancer patient-derived organoids at low micromolar concentrations. Compound 1a effectively inhibits the growth of non-small-cell lung cancer and triple-negative breast cancer xenograft tumors, impedes the metastatic spread of breast cancer cells, and can be modified into an antibody-drug conjugate payload to achieve precise tumor delivery in mice. Identified by thermal proteome profiling, an important molecular target of 1a in cellulo is Girdin, a multifunctional adaptor protein that is overexpressed in cancer cells and unequivocally serves as a signaling hub for multiple pivotal oncogenic pathways. However, specific small-molecule inhibitors of Girdin have not yet been developed. Notably, 1a exhibits high binding affinity to Girdin with a Kd of 1.3 μM and targets the Girdin-linked EGFR/AKT/mTOR/STAT3 cancer-driving pathway, inhibiting cancer cell proliferation and metastatic activity. Our study reveals a potent Girdin-targeting anticancer compound and demonstrates that octahedral metal complexes constitute an untapped library of small-molecule inhibitors that can fit into the ligand-binding pockets of key oncoproteins. |
Persistent Identifier | http://hdl.handle.net/10722/348552 |
ISSN | 2023 Impact Factor: 9.4 2023 SCImago Journal Rankings: 3.737 |
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Ruan, Mei Ling | - |
dc.contributor.author | Ni, Wen Xiu | - |
dc.contributor.author | Chu, Jacky C.H. | - |
dc.contributor.author | Lam, Tsz Lung | - |
dc.contributor.author | Law, Kwok Chung | - |
dc.contributor.author | Zhang, Yiwei | - |
dc.contributor.author | Yang, Guanya | - |
dc.contributor.author | He, Ying | - |
dc.contributor.author | Zhang, Chunlei | - |
dc.contributor.author | Eva Fung, Yi Man | - |
dc.contributor.author | Liu, Tao | - |
dc.contributor.author | Huang, Tao | - |
dc.contributor.author | Lok, Chun Nam | - |
dc.contributor.author | Chan, Sharon Lai Fung | - |
dc.contributor.author | Che, Chi Ming | - |
dc.date.accessioned | 2024-10-10T00:31:31Z | - |
dc.date.available | 2024-10-10T00:31:31Z | - |
dc.date.issued | 2024-06-11 | - |
dc.identifier.citation | Proceedings of the National Academy of Sciences, 2024, v. 121, n. 25 | - |
dc.identifier.issn | 0027-8424 | - |
dc.identifier.uri | http://hdl.handle.net/10722/348552 | - |
dc.description.abstract | <p>Many cancer-driving protein targets remain undruggable due to a lack of binding molecular scaffolds. In this regard, octahedral metal complexes with unique and versatile three-dimensional structures have rarely been explored as inhibitors of undruggable protein targets. Here, we describe antitumor iridium(III) pyridinium-N-heterocyclic carbene complex 1a, which profoundly reduces the viability of lung and breast cancer cells as well as cancer patient-derived organoids at low micromolar concentrations. Compound 1a effectively inhibits the growth of non-small-cell lung cancer and triple-negative breast cancer xenograft tumors, impedes the metastatic spread of breast cancer cells, and can be modified into an antibody-drug conjugate payload to achieve precise tumor delivery in mice. Identified by thermal proteome profiling, an important molecular target of 1a in cellulo is Girdin, a multifunctional adaptor protein that is overexpressed in cancer cells and unequivocally serves as a signaling hub for multiple pivotal oncogenic pathways. However, specific small-molecule inhibitors of Girdin have not yet been developed. Notably, 1a exhibits high binding affinity to Girdin with a Kd of 1.3 μM and targets the Girdin-linked EGFR/AKT/mTOR/STAT3 cancer-driving pathway, inhibiting cancer cell proliferation and metastatic activity. Our study reveals a potent Girdin-targeting anticancer compound and demonstrates that octahedral metal complexes constitute an untapped library of small-molecule inhibitors that can fit into the ligand-binding pockets of key oncoproteins.</p> | - |
dc.language | eng | - |
dc.publisher | National Academy of Sciences | - |
dc.relation.ispartof | Proceedings of the National Academy of Sciences | - |
dc.subject | anticancer compounds | - |
dc.subject | Girdin | - |
dc.subject | iridium | - |
dc.subject | N-heterocyclic carbene | - |
dc.title | Iridium(III) carbene complexes as potent girdin inhibitors against metastatic cancers | - |
dc.type | Article | - |
dc.identifier.doi | 10.1073/pnas.2316615121 | - |
dc.identifier.pmid | 38861602 | - |
dc.identifier.scopus | eid_2-s2.0-85195888081 | - |
dc.identifier.volume | 121 | - |
dc.identifier.issue | 25 | - |
dc.identifier.eissn | 1091-6490 | - |
dc.identifier.issnl | 0027-8424 | - |