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Title: Discovery and optimisation of small-molecule ERK5 inhibitors as cancer therapeutics
Author: Myers, Stephanie May
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2013
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Extracellular signal-regulated kinase 5 (ERK5) is a member of the protein kinase superfamily, which plays an essential role in the transduction of extracellular signals to intracellular effectors. Activation of the ERK5 signalling pathway is associated with cell survival, proliferation, and differentiation, and thus ERK5 over-expression may have implications in carcinogenesis. Therefore, the discovery and development of small molecule inhibitors of ERK5 may offer a novel therapeutic intervention for cancer. High throughput screening (HTS) of chemical libraries, conducted by Cancer Research Technology, revealed three distinct chemical series as moderate inhibitors of ERK5. Two of these series are described herein i.e.: 3-cyanopyridines (IC50 = 0.5 – 31.3 μM); and pyrrolecarboxamides (IC50 = 0.66 – 3.5 μM). Two 3-cyanopyridine based hits (2-(2-((3-cyano-4-(4-fluorophenyl)-6-phenylpyridin-2- yl)thio)acetamido)acetic acid, 68 and 2-((3-cyano-4-(4-fluorophenyl)-6-phenylpyridin-2- yl)thio)-N-(2-oxopropyl)acetamide, 67; IC50 values = 1.6 and 0.5 μM, respectively) were resynthesised and were slightly less active at 4.9 and 20.5 μM. The 3-cyanopyridine scaffold was deemed a valid starting point for initiating structure activity relationship (SAR) studies. Three areas were identified for further investigation i.e.: modification to the thioether sidechain; modification to the aryl substituent; and isosteric replacement of the 3-cyano motif. Structure-activity studies did not result in improved potency over the initial hits. Previously, the pyrrole-carboxamide series has been validated successfully. Hit-to-lead studies around the aroyl ring highlighted the importance of substitution pattern for potency, with 2,6-difluoro (or 2,3-dichloro) substituents conferring the greatest potency (4-(2,6- difluorobenzoyl)-N-(pyridin-4-ylmethyl)-1H-pyrrole-2-carboxamide, 144; IC50 = 2.3 μM) initially. Truncation of the carboxamide side-chain resulted in improved activity (IC50 = 0.9 4 μM) and crucially, ≥100-fold selectivity for ERK5 over the closely related kinase p38α was also achieved e.g. 4-(2,6-difluorobenzoyl)-N-(pyridin-4-yl)-1H-pyrrole-2-carboxamide, 256. Tuning of the aroyl substituents and pyridyl groups resulted in discovery of 4-(2-bromo-6- fluorobenzoyl)-N-(pyridin-3-yl)-1H-pyrrole-2-carboxamide, 278 a potent and selective ERK5 inhibitor with excellent drug-like properties (i.e.: MW = 388; cLogP = 3.2; LE = 0.35; Aqueous solubility = >100 μM; PPB = 94%). Preliminary in vivo studies of lead compound 4-(2-bromo-6-fluorobenzoyl)-N-(pyridin-3-yl)-1H-pyrrole-2-carboxamide have confirmed efficacy in xenograft tumour models, and satisfactory pharmacokinetic properties in mice. The pyrrole-carboxamide series has now entered the lead optimisation phase of drug discovery, focussing on improvement of cellular activity, and eliminating CYP inhibition, with the aim of providing compounds with suitable potency and properties for clinical trials.
Supervisor: Not available Sponsor: Cancer Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available