ponatinib   

GtoPdb Ligand ID: 5890

Synonyms: AP24534 | Iclusig®
ponatinib is an approved drug (FDA (2012), EMA (2013))
Compound class: Synthetic organic
Comment: Ponatinib is a Type-1 kinase inhibitor. It is a third generation BCR-Abl inhibitor. Use of ponatinib is subject to additional monitoring due to the observed serious risk of liver problems or blood clots (including heart attack and stroke, collectively referred to as arterial occlusive events, or AOEs). Final 5-year results of safety and efficacy in Ph+ leukemia as evaluated in NCT01207440 are reported by Cortes et al. (2018) [1].
Marketed formulations contain ponatinib hydrochloride (PubChem CID 46908927).
Ponatinib has also been reported as a dual inhibitor of RIPK1 and RIPK3 which inhibits experimental models of RIPK1- and RIPK3-dependent cell death (necroptosis) [5]. On the basis of these findings, hybrid ponatinib/necrostatin-1 (a RIPK1 and IDO inhibitor) were designed and tested for potential to target RIPK1- and RIPK3-driven inflammatory pathologies.
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2D Structure
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Physico-chemical Properties
Hydrogen bond acceptors 6
Hydrogen bond donors 1
Rotatable bonds 6
Topological polar surface area 65.77
Molecular weight 532.22
XLogP 5.2
No. Lipinski's rules broken 1
SMILES / InChI / InChIKey
Canonical SMILES CN1CCN(CC1)Cc1ccc(cc1C(F)(F)F)NC(=O)c1ccc(c(c1)C#Cc1cnc2n1nccc2)C
Isomeric SMILES CN1CCN(CC1)Cc1ccc(cc1C(F)(F)F)NC(=O)c1ccc(c(c1)C#Cc1cnc2n1nccc2)C
InChI InChI=1S/C29H27F3N6O/c1-20-5-6-22(16-21(20)8-10-25-18-33-27-4-3-11-34-38(25)27)28(39)35-24-9-7-23(26(17-24)29(30,31)32)19-37-14-12-36(2)13-15-37/h3-7,9,11,16-18H,12-15,19H2,1-2H3,(H,35,39)
InChI Key PHXJVRSECIGDHY-UHFFFAOYSA-N
References
1. Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre PD, Paquette R, Chuah C, Nicolini FE, Apperley JF, Khoury HJ, Talpaz M et al.. (2018)
Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial.
Blood, 132 (4): 393-404. [PMID:29567798]
2. Dale T, Clarke PA, Esdar C, Waalboer D, Adeniji-Popoola O, Ortiz-Ruiz MJ, Mallinger A, Samant RS, Czodrowski P, Musil D et al.. (2015)
A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease.
Nat. Chem. Biol., 11 (12): 973-80. [PMID:26502155]
3. Huang WS, Metcalf CA, Sundaramoorthi R, Wang Y, Zou D, Thomas RM, Zhu X, Cai L, Wen D, Liu S et al.. (2010)
Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-abelson (BCR-ABL) kinase including the T315I gatekeeper mutant.
J. Med. Chem., 53 (12): 4701-19. [PMID:20513156]
4. Mologni L, Redaelli S, Morandi A, Plaza-Menacho I, Gambacorti-Passerini C. (2013)
Ponatinib is a potent inhibitor of wild-type and drug-resistant gatekeeper mutant RET kinase.
Mol. Cell. Endocrinol., 377 (1-2): 1-6. [PMID:23811235]
5. Najjar M, Suebsuwong C, Ray SS, Thapa RJ, Maki JL, Nogusa S, Shah S, Saleh D, Gough PJ, Bertin J et al.. (2015)
Structure guided design of potent and selective ponatinib-based hybrid inhibitors for RIPK1.
Cell Rep, 10 (11): 1850-60. [PMID:25801024]
6. Willemsen-Seegers N, Uitdehaag JCM, Prinsen MBW, de Vetter JRF, de Man J, Sawa M, Kawase Y, Buijsman RC, Zaman GJR. (2017)
Compound Selectivity and Target Residence Time of Kinase Inhibitors Studied with Surface Plasmon Resonance.
J. Mol. Biol., 429 (4): 574-586. [PMID:28043854]