Tanzisertib

Alzheimer's disease (AD) is a complex neurological disorder and no effective drug is available for its treatment. Numerous pathological conditions are believed to be responsible for the initiation and development of AD including c-Jun N-terminal kinases (JNKs). The JNKs are one of the enzymes from the mitogen-activated protein kinase (MAPK) family that controls the phosphorylation of various transcription factors on serine and threonine residues, and hold significant responsibilities in tasks like gene expression, cell proliferation, differentiation, and apoptosis. Since, JNK3 is primarily expressed in the brain hence its increased levels in the brain are associated with the AD pathology promoting neurofibrillary tangles, senile plaques, neuroinflammation, and nerve cell apoptosis. The current research work is focused on the development of novel JNK inhibitors as therapeutics for AD employing a structure-based virtual screening (SBVS) approach. The ZINC database (14634052 compounds) was investigated after employing pan assay interference (PAINs), drug-likeness, and diversity picking filter to distinguish molecules interacting with JNK3 by following three docking precision criteria: High Throughput Virtual Screening (HTVS), Standard Precision (SP), and Extra Precision (XP) & MMGBSA. Five lead molecules showed a better docking score in the range of -13.091 to -14.051 kcal/mol better than the reference compound (- 11.828 kcal/mol). The lead compounds displayed acceptable pharmacokinetic properties and were subjected to molecular dynamic simulations of 100 ns and binding free energy calculations. All the lead molecules showed stable RMSD and hydrogen bond interactions throughout the trajectory. The ∆G_MM/PBSA__total score for the lead compounds ZINC220382956, ZINC147071339, ZINC207081127, ZINC205151456, ZINC1228819126, and CC-930 was calculated and found to be - 31.39, - 42.8, - 37.04, - 39.01, - 36.5, - 34.16 kcal/mol, respectively. Thus, it was concluded that the lead molecules identified in these studies have the potential to be explored as potent JNK3 inhibitors.

Activation of the JUN amino-terminal kinase (JNK) pathway is prominent in most forms of acute and progressive tubulointerstitial damage, including acute renal ischemia/reperfusion injury (IRI). Two forms of JNK, JNK1 and JNK2, are expressed in the kidney. Systemic administration of pan-JNK inhibitors suppresses renal IRI; however, the contribution of JNK1 versus JNK2, and the specific role of JNK activation in the proximal tubule in IRI, remains unknown. These questions were addressed in rat and mouse models of acute bilateral renal IRI. Administration of the JNK inhibitor, CC-930, substantially reduced the severity of renal failure, tubular damage, and inflammation at 24 hours in a rat IRI model. Additionally, Jnk1^-/- mice, but not Jnk2^-/- mice, were shown to be significantly protected against acute renal failure, tubular damage, and inflammation in the IRI model. Furthermore, mice with conditional Jnk1 deletion in the proximal tubule also showed considerable protection from IRI-induced renal failure, tubular damage, and inflammation. Finally, primary cultures of Jnk1^-/-, but not Jnk2^-/-, tubular epithelial cells were protected from oxidant-induced cell death, in association with preventing phosphorylation of proteins (receptor interacting serine/threonine kinase 3 and mixed lineage kinase domain-like pseudokinase) in the necroptosis pathway. In conclusion, JNK1, but not JNK2, plays a specific role in IRI-induced cell death in the proximal tubule, leading to acute renal failure.