Synthesis of Thiazolo[5,4-f]quinazolin-9(8H)-ones as Multi-Target Directed Ligands of Ser/Thr Kinases

International audienceA library of thirty novel thiazolo[5,4-f]quinazolin-9(8H)-one derivatives belonging to four series designated as 12, 13, 14 and 15 was efficiently prepared, helped by microwave-assisted technology when required. The efficient multistep synthesis of methyl 6-amino-2-cyano- benzo[d]thiazole-7-carboxylate (1) has been reinvestigated and performed on a multigram scale. The inhibitory potency of the final products against five kinases involved in Alzheimer’s disease was evaluated. This study demonstrates that some molecules of the 12 and 13 series described in this paper are particularly promising for the development of new multi-target inhibitors of kinase

Synthesis of bioactive 2-(arylamino)thiazolo[5,4-f]-quinazolin-9-ones via the Hügershoff reaction or Cu- catalyzed intramolecular C-S bond formation

International audienceA library of thirty eight novel thiazolo[5,4-f]quinazolin-9(8H)-one derivatives (series 8, 10, 14 and 17) was prepared via the Hügershoff reaction and a Cu catalyzed intramolecular C-S bond formation, helped by microwave-assisted technology when required. The efficient multistep synthesis of the key 6-amino-3-cyclopropylquinazolin-4(3H)-one (3) has been reinvestigated and performed on a multigram scale from the starting 5-nitroanthranilic acid. The inhibitory potency of the final products was evaluated against five kinases involved in Alzheimer’s disease and showed that some molecules of the 17 series described in this paper are particularly promising for the development of novel multi-target inhibitors of kinases

Molecular structures of cdc2-like kinases in complex with a new inhibitor chemotype

Cdc2-like kinases (CLKs) represent a family of serine-threonine kinases involved in the regulation of splicing by phosphorylation of SR-proteins and other splicing factors. Although compounds acting against CLKs have been described, only a few show selectivity against dual-specificity tyrosine phosphorylation regulated-kinases (DYRKs). We here report a novel CLK inhibitor family based on a 6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one core scaffold. Within the series, 3-(3-chlorophenyl)-6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one (KuWal151) was identified as inhibitor of CLK1, CLK2 and CLK4 with a high selectivity margin towards DYRK kinases. The compound displayed a potent antiproliferative activity in an array of cultured cancer cell lines. The X-ray structure analyses of three members of the new compound class co-crystallized with CLK proteins corroborated a molecular binding mode predicted by docking studies

New insight in ARX-mutated patients' language specific impairment and underlying FOXP1 dysregulation

Numéro spécial Abstracts of EPNS 2017 - 12th European Paediatric Neurology Society CongressLyon, France20- 24 June 2017 12th European Paediatric Neurology Society Congress, 20 - 24 June 2017International audienceObjective: The ARX (Aristaless Related homeoboX) gene encodes a transcription factor which mutations have been associated with syndromes ranging from severe neuronal migration defects such as lissencephaly, to mild or moderate forms of X-linked Intellectual Disability (ID) without apparent brain abnormalities. The most frequent ARX mutation (c.429_452dup24), a duplication of 24 base pairs, constitutes a recognizable clinical syndrome with ARX patients exhibiting ID, without primary motor impairment, but with a very specific upper limb distal motor apraxia associated with a pathognomonic hand-grip. Furthermore, patients also exhibit language impairment and an obvious difficulty to execute oro-lingual praxis. The aim of the present study was to better characterize language abnormalities in ARX c.429_452dup24 patients. Methods: We collected data on 16 French ARX patients, and 16 age- and IQ-matched controls (Fragile X (FraX) patients). Given the similarities between ARX mutated patients and FOXP2-mutated patients, we investigated the molecular relationship between Arx and Foxp2. Results: ARX patients have structural language impairments in both receptive and expressive aspects of language compared to FraX patients: phonetic feature recognition, receptive (ECOSSE test for sentence comprehension) and expressive (TCG-R for sentence production) morphosyntactic skills and oro-lingual dyspraxia (movements of the face, tongue, and lips) were significantly more impaired in ARX patients. FraX patients made words more complex and they were less impaired in their ability to articulate words. On the contrary, language pragmatic analysis showed that ARXdup24 patients had significantly better interactional skills than FraX. patients. Interestingly, we found that although Arx has no effect on Foxp2 expression, Arx was found to activate Foxp1 expression, and that the c.429_452dup24 mutation alters the expression of this gene. Foxp1 is known to heterodimerize with Foxp2 and has been involved in language defects. Conclusion: These data uncover a novel role of ARX in language development, probably through the regulation of Foxp1

CDK/CK1 inhibitors roscovitine and CR8 down-regulate amplified MYCN in neuroblastoma cells

To understand the mechanisms of action of (R)-roscovitine and (S)-CR8, two related pharmacological inhibitors of cyclin-dependent kinases (CDKs), we applied a variety of ‘-omics’ techniques to the human neuroblastoma SH-SY5Y and IMR32 cell lines: (1) kinase interaction assays, (2) affinity competition on immobilized broad-spectrum kinase inhibitors, (3) affinity chromatography on immobilized (R)-roscovitine and (S)-CR8, (4) whole genome transcriptomics analysis and specific quantitative PCR studies, (5) global quantitative proteomics approach and western blot analysis of selected proteins. Altogether, the results show that the major direct targets of these two molecules belong to the CDKs (1,2,5,7,9,12), DYRKs, CLKs and CK1s families. By inhibiting CDK7, CDK9 and CDK12, these inhibitors transiently reduce RNA polymerase 2 activity, which results in downregulation of a large set of genes. Global transcriptomics and proteomics analysis converge to a central role of MYC transcription factors downregulation. Indeed, CDK inhibitors trigger rapid and massive downregulation of MYCN expression in MYCN-amplified neuroblastoma cells as well as in nude mice xenografted IMR32 cells. Inhibition of casein kinase 1 may also contribute to the antitumoral activity of (R)-roscovitine and (S)-CR8. This dual mechanism of action may be crucial in the use of these kinase inhibitors for the treatment of MYC-dependent cancers, in particular neuroblastoma where MYCN amplification is a strong predictor factor for high-risk disease