| Structural highlights
Function
[PIR_HUMAN] Possible transcriptional coregulator. May contribute to the regulation of cellular processes via its interaction with BCL3. May be required for efficient terminal myeloid maturation of hematopoietic cells. May play a role in the regulation of cell migration. May promote apoptosis when overexpressed. Has quercetin 2,3-dioxygenase activity (in vitro).[1] [2] [3] [4]
Publication Abstract from PubMed
Polypharmacology is often a key contributor to the efficacy of a drug, but is also a potential risk. We investigated two hits discovered via a cell-based phenotypic screen, the CDK9 inhibitor CCT250006 (1) and the pirin ligand CCT245232 (2), to establish methodology to elucidate their secondary protein targets. Using computational pocket-based analysis, we discovered intrafamily polypharmacology for our kinase inhibitor, despite little overall sequence identity. The interfamily polypharmacology of 2 with B-Raf was used to discover a novel pirin ligand from a very small but privileged compound library despite no apparent ligand or binding site similarity. Our data demonstrates that in areas of drug discovery where intrafamily polypharmacology is often an issue, ligand dissimilarity cannot necessarily be used to assume different off-target profiles and that understanding interfamily polypharmacology will be important in the future to reduce the risk of idiopathic toxicity and in the design of screening libraries.
Privileged Structures and Polypharmacology within and between Protein Families.,Meyers J, Chessum NEA, Ali S, Mok NY, Wilding B, Pasqua AE, Rowlands M, Tucker MJ, Evans LE, Rye CS, O'Fee L, Le Bihan YV, Burke R, Carter M, Workman P, Blagg J, Brown N, van Montfort RLM, Jones K, Cheeseman MD ACS Med Chem Lett. 2018 Nov 16;9(12):1199-1204. doi:, 10.1021/acsmedchemlett.8b00364. eCollection 2018 Dec 13. PMID:30613326[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wendler WM, Kremmer E, Forster R, Winnacker EL. Identification of pirin, a novel highly conserved nuclear protein. J Biol Chem. 1997 Mar 28;272(13):8482-9. PMID:9079676
- ↑ Gelbman BD, Heguy A, O'Connor TP, Zabner J, Crystal RG. Upregulation of pirin expression by chronic cigarette smoking is associated with bronchial epithelial cell apoptosis. Respir Res. 2007 Feb 8;8:10. PMID:17288615 doi:http://dx.doi.org/10.1186/1465-9921-8-10
- ↑ Licciulli S, Cambiaghi V, Scafetta G, Gruszka AM, Alcalay M. Pirin downregulation is a feature of AML and leads to impairment of terminal myeloid differentiation. Leukemia. 2010 Feb;24(2):429-37. doi: 10.1038/leu.2009.247. Epub 2009 Dec 10. PMID:20010624 doi:http://dx.doi.org/10.1038/leu.2009.247
- ↑ Miyazaki I, Simizu S, Okumura H, Takagi S, Osada H. A small-molecule inhibitor shows that pirin regulates migration of melanoma cells. Nat Chem Biol. 2010 Sep;6(9):667-73. Epub 2010 Aug 15. PMID:20711196 doi:10.1038/nchembio.423
- ↑ Meyers J, Chessum NEA, Ali S, Mok NY, Wilding B, Pasqua AE, Rowlands M, Tucker MJ, Evans LE, Rye CS, O'Fee L, Le Bihan YV, Burke R, Carter M, Workman P, Blagg J, Brown N, van Montfort RLM, Jones K, Cheeseman MD. Privileged Structures and Polypharmacology within and between Protein Families. ACS Med Chem Lett. 2018 Nov 16;9(12):1199-1204. doi:, 10.1021/acsmedchemlett.8b00364. eCollection 2018 Dec 13. PMID:30613326 doi:http://dx.doi.org/10.1021/acsmedchemlett.8b00364
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