2899-29-8Relevant articles and documents
Illuminating a Dark Kinase: Structure-Guided Design, Synthesis, and Evaluation of a Potent Nek1 Inhibitor and Its Effects on the Embryonic Zebrafish Pronephros
Baumann, Georg,Meckel, Tobias,B?hm, Kevin,Shih, Yung-Hsin,Dickhaut, Mirco,Reichardt, Torben,Pilakowski, Johannes,Pehl, Ulrich,Schmidt, Boris
, (2021/04/12)
NIMA-related kinase 1 (Nek1) has lately garnered attention for its widespread function in ciliogenesis, apoptosis, and the DNA-damage response. Despite its involvement in various diseases and its potential as a cancer drug target, no directed medicinal chemistry efforts toward inhibitors against this dark kinase are published. Here, we report the structure-guided design of a potent small-molecule Nek1 inhibitor, starting from a scaffold identified by kinase cross-screening analysis. Seven lead compounds were identified in silico and evaluated for their inhibitory activity. The top compound, 10f, was further profiled for efficacy, toxicity, and bioavailability in a zebrafish polycystic kidney disease model. Administration of 10f caused the expansion of fluorescence-labeled proximal convoluted tubules, supporting our hypothesis that Nek1-inhibition causes cystic kidneys in zebrafish embryos. Compound 10f displayed insignificant inhibition in 48 of 50 kinases in a selectivity test panel. The findings provide a powerful tool to further elucidate the function and pharmacology of this neglected kinase.
Total syntheses of Hexahydropyrrolo[2,3-b]indole Alkaloids, (+)-pseudophrynamine 270 and (+)-pseudophrynamine 272A
Maity, Arindam,Munda, Mintu,Niyogi, Sovan,Kumar, Nivesh,Bisai, Alakesh
, (2021/12/09)
A general strategy for asymmetric approach to the hexahydropyrrolo[2,3-b]indole alkaloids sharing a vicinal quaternary-tertiary centers has been disclosed via Pd(0)-catalyzed N-deacylative allylations (N-DaA) (dr > 20:1). Utilizing this strategy, asymmetric total syntheses of pseudophrynamines 270 (3c) and 272A (3b) have been achieved from a 3-substituted N-acyl indole 8 (pro-nucleophile) with allyl alcohol (pro-electrophile).
An increase in side-group hydrophobicity largely improves the potency of ritonavir-like inhibitors of CYP3A4
Samuels, Eric R.,Sevrioukova, Irina F.
, (2020/02/13)
Identification of structural determinants required for potent inhibition of drug-metabolizing cytochrome P450 3A4 (CYP3A4) could help develop safer drugs and more effective pharmacoenhancers. We utilize a rational inhibitor design to decipher structure-activity relationships in analogues of ritonavir, a highly potent CYP3A4 inhibitor marketed as pharmacoenhancer. Analysis of compounds with the R1 side-group as phenyl or naphthalene and R2 as indole or naphthalene in different stereo configuration showed that (i) analogues with the R2-naphthalene tend to bind tighter and inhibit CYP3A4 more potently than the R2-phenyl/indole containing counterparts; (ii) stereochemistry becomes a more important contributing factor, as the bulky side-groups limit the ability to optimize protein-ligand interactions; (iii) the relationship between the R1/R2 configuration and preferential binding to CYP3A4 is complex and depends on the side-group functionality/interplay and backbone spacing; and (iv) three inhibitors, 5a-b and 7d, were superior to ritonavir (IC50 of 0.055–0.085 μM vs. 0.130 μM, respectively).
