Should Cardiosafety be Ruled by hERG Inhibition? Early Testing Scenarios and Integrated Risk Assessment

Михайлов, Д. В.; Traebert, Martin; Lü, Qiang; Whitebread, Steven; Egan, William J.

doi:10.1002/9783527627448.ch16

Cited by 2 publications

(1 citation statement)

References 102 publications

(103 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Reduction of the potential cardiac safety risk associated with hERG inhibition was considered a key priority . Although several ion currents and channels are involved in the cardiac action potential, we will here only discuss the derisking strategy for QT prolongation based on minimization of hERG inhibition, since it is well established that preclinical studies measuring hERG current are predictive for QT prolongation in patients. , With the aim of reducing the hERG activity of compound 7 without reducing potency, we synthesized analogs in which the pyrimidine ring was replaced by other moieties. From the crystal structure of 7 (Figure E) we discerned that the pyrimidine was in close proximity to the backbone carbonyl group of glutamic acid E481.…”

Section: From Lead Compound 7 To Clinical Candidatementioning

confidence: 99%

Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1

et al. 2018

View full text Add to dashboard Cite

Chronic myelogenous leukemia (CML) arises from the constitutive activity of the BCR-ABL1 oncoprotein. Tyrosine kinase inhibitors (TKIs) that target the ATP-binding site have transformed CML into a chronic manageable disease. However, some patients develop drug resistance due to ATP-site mutations impeding drug binding. We describe the discovery of asciminib (ABL001), the first allosteric BCR-ABL1 inhibitor to reach the clinic. Asciminib binds to the myristate pocket of BCR-ABL1 and maintains activity against TKI-resistant ATP-site mutations. Although resistance can emerge due to myristate-site mutations, these are sensitive to ATP-competitive inhibitors so that combinations of asciminib with ATP-competitive TKIs suppress the emergence of resistance. Fragment-based screening using NMR and X-ray yielded ligands for the myristate pocket. An NMR-based conformational assay guided the transformation of these inactive ligands into ABL1 inhibitors. Further structure-based optimization for potency, physicochemical, pharmacokinetic, and drug-like properties, culminated in asciminib, which is currently undergoing clinical studies in CML patients.

show abstract