Discovery of imidazo[1,2-a]pyridine-thiophene derivatives as FLT3 and FLT3 mutants inhibitors for acute myeloid leukemia through structure-based optimization of an NEK2 inhibitor.

FMS-like tyrosine kinase 3 (FLT3) with an internal tandem duplication (ITD) mutation has been validated as a driver lesion and a therapeutic target for acute myeloid leukemia (AML). Currently, several potent small-molecule FLT3 kinase inhibitors are being evaluated or have completed evaluation in clinical trials. However, many of these inhibitors are challenged by the secondary mutations on kinase domain, especially the point mutations at the activation loop (D835) and gatekeeper residue (F691). To overcome the resistance challenge, we identified a novel series of imidazo[1,2-a]pyridine-thiophene derivatives from a NIMA-related kinase 2 (NEK2) kinase inhibitor CMP3a, which retained inhibitory activities on FTL3-ITDD835V and FLT3-ITDF691L. Through this study, we identified the imidazo[1,2-a]pyridine-thiophene derivatives as type-I inhibitors of FLT3. Moreover, we observed compound 5o as an inhibitor displaying equal anti-proliferative activities against FLT3-ITD, FTL3-ITDD835Y and FLT3-ITDF691L driven acute myeloid leukemia (AML) cell lines. Meanwhile, the apoptotic effects of compound supported its mechanism of anti-proliferative action. These results indicate that the imidazo[1,2-a]pyridine-thiophene scaffold is promising for targeting acquired resistance caused by FLT3 secondary mutations and compound 5o is an interesting lead in this direction.

Targeted activity of the small molecule kinase inhibitor Pz-1 towards RET and TRK kinases.

We have recently described Pz-1, a benzimidazole-based type-2 RET and VEGFR2 inhibitor. Based on a kinome scan, here we show that Pz-1 is also a potent (IC50 < 1 nM) TRKA/B/C inhibitor. Pz-1 potently inhibited proliferation of human cancer cells carrying either RET- or TRKA oncoproteins (IC50 ~ 1 nM), with a negligible effect against RET- and TRKA-negative cells. By testing mutations, known to mediate resistance to other compounds, RET G810R/S, but not L730I/V, E732K, V738A and Y806N, showed some degree of resistance to Pz-1. In the case of TRKA, G595R and F589L, but not G667C, showed some degree of resistance. In xenograft models, orally administered Pz-1 almost completely inhibited RET- and TRKA-mutant tumours at 1-3 mg/kg/day but showed a reduced effect on RET/TRKA-negative cancer models. The activity, albeit reduced, on RET/TRKA-negative tumours may be justified by VEGFR2 inhibition. Tumours induced by NIH3T3 cells transfected by RET G810R and TRKA G595R featured resistance to Pz-1, demonstrating that RET or TRKA inhibition is critical for its anti-tumourigenic effect. In conclusion, Pz-1 represents a new powerful kinase inhibitor with distinct activity towards cancers induced by oncogenic RET and TRKA variants, including some mutants displaying resistance to other drugs.

Microwave-assisted facile construction of quinoxalinone and benzimidazopyrazinone derivatives via two paths of post-Ugi cascade reaction.

A facile and efficient route to synthesize quinoxalinone and benzimidazopyrazinone was developed via two paths of a post-Ugi cascade reaction. By simply alternating the order of nucleophilic substitution reactions, both heterocycles could be accessed selectively from the same Ugi adduct. Microwave-assisted synthesis protocol provided these compounds with one purification procedure for three steps. These two scaffolds with more possible spaces for further modifications provide great benefit toward combinatorial and medicinal chemistry campaigns.

Selective, C-3 Friedel-Crafts acylation to generate functionally diverse, acetylated Imidazo[1,2-a]pyridine derivatives.

Carbon-carbon bonds are integral for pharmaceutical discovery and development. Frequently, C-C bond reactions utilize expensive catalyst/ligand combinations and/or are low yielding, which can increase time and expenditures in pharmaceutical development. To enhance C-C bond formation protocols, we developed a highly efficient, selective, and combinatorially applicable Friedel-Crafts acylation to acetylate the C-3 position of imidazo[1,2-a]pyridines. The reaction, catalyzed by aluminum chloride, is both cost effective and more combinatorial friendly compared to acetylation reactions requiring multiple, stoichiometric equivalents of AlCl3. The protocol has broad application in the construction of acetylated imidazo[1,2-a]pyridines with an extensive substrate scope. All starting materials are common and the reaction requires inexpensive, conventional heating methods for adaptation in any laboratory. Further, the synthesized compounds are predicted to possess GABA activity through a validated, GABA binding model. The developed method serves as a superior route to generate C-3 acetylated imidazo[1,2-a]pyridine building-blocks for combinatorial synthetic efforts.

Rational Design, Synthesis and Biological Evaluation of Pyrimidine-4,6-diamine derivatives as Type-II inhibitors of FLT3 Selective Against c-KIT.

FMS-like Tyrosine Kinase 3 (FLT3) is a clinically validated target for acute myeloid leukemia (AML). Inhibitors targeting FLT3 have been evaluated in clinical studies and have exhibited potential to treat FLT3-driven AML. A frequent, clinical limitation is FLT3 selectivity, as concomitant inhibition of FLT3 and c-KIT is thought to cause dose-limiting myelosuppression. Through a rational design approach, novel FLT3 inhibitors were synthesized employing a pyridine/pyrimidine warhead. The most potent compound identified from the studies is compound 13a, which exhibited an IC50 value of 13.9 ± 6.5 nM against the FLT3 kinase with high selectivity over c-KIT. Mechanism of action studies suggested that 13a is a Type-II kinase inhibitor, which was also supported through computer aided drug discovery (CADD) efforts. Cell-based assays identified that 13a was potent on a variety of FLT3-driven cell lines with clinical relevance. We report herein the discovery and therapeutic evaluation of 4,6-diamino pyrimidine-based Type-II FLT3 inhibitors, which can serve as a FLT3-selective scaffold for further clinical development.

Synthesis of Constrained Heterocycles Employing Two Post-Ugi Cyclization Methods for Rapid Library Generation with In Cellulo Activity.

Benzimidazoles and quinoxalinones are present in the core of many pharmacologically relevant compounds. Several combinatorial methods have been developed to attach ring systems to both scaffolds for derivatization at select positions. Herein, we describe the development of novel constrained heterocyclic compounds attached to the N1 position of both benzimidazole and quinoxalinone scaffolds. Utilizing robust post-Ugi cyclization methods, including the Ugi-deprotection-cyclization (UDC) methodology, allows for efficient access to a new area of chemical space. Additionally, molecular modeling and in cellulo screening was employed to therapeutically validate the compounds formed with this method.

A 17-billion-solar-mass black hole in a group galaxy with a diffuse core.

Quasars are associated with and powered by the accretion of material onto massive black holes; the detection of highly luminous quasars with redshifts greater than z = 6 suggests that black holes of up to ten billion solar masses already existed 13 billion years ago. Two possible present-day 'dormant' descendants of this population of 'active' black holes have been found in the galaxies NGC 3842 and NGC 4889 at the centres of the Leo and Coma galaxy clusters, which together form the central region of the Great Wall--the largest local structure of galaxies. The most luminous quasars, however, are not confined to such high-density regions of the early Universe; yet dormant black holes of this high mass have not yet been found outside of modern-day rich clusters. Here we report observations of the stellar velocity distribution in the galaxy NGC 1600--a relatively isolated elliptical galaxy near the centre of a galaxy group at a distance of 64 megaparsecs from Earth. We use orbit superposition models to determine that the black hole at the centre of NGC 1600 has a mass of 17 billion solar masses. The spatial distribution of stars near the centre of NGC 1600 is rather diffuse. We find that the region of depleted stellar density in the cores of massive elliptical galaxies extends over the same radius as the gravitational sphere of influence of the central black holes, and interpret this as the dynamical imprint of the black holes.

One-Pot Two-Step Multicomponent Process of Indole and Other Nitrogenous Heterocycles or Amines toward α-Oxo-acetamidines.

A cesium carbonate promoted three-component reaction of N-H containing heterocycles, primary or secondary amines, arylglyoxaldehydes, and anilines is reported. The key step involves a tandem sequence of N-1 addition of a heterocycle or an amine to preformed α-iminoketones, followed by an air- or oxygen-mediated oxidation to form α-oxo-acetamidines. The scope of the reaction is enticingly broad, and this novel methodology is applied toward the synthesis of various polycyclic heterocycles.

Two ten-billion-solar-mass black holes at the centres of giant elliptical galaxies.

Observational work conducted over the past few decades indicates that all massive galaxies have supermassive black holes at their centres. Although the luminosities and brightness fluctuations of quasars in the early Universe suggest that some were powered by black holes with masses greater than 10 billion solar masses, the remnants of these objects have not been found in the nearby Universe. The giant elliptical galaxy Messier 87 hosts the hitherto most massive known black hole, which has a mass of 6.3 billion solar masses. Here we report that NGC 3842, the brightest galaxy in a cluster at a distance from Earth of 98 megaparsecs, has a central black hole with a mass of 9.7 billion solar masses, and that a black hole of comparable or greater mass is present in NGC 4889, the brightest galaxy in the Coma cluster (at a distance of 103 megaparsecs). These two black holes are significantly more massive than predicted by linearly extrapolating the widely used correlations between black-hole mass and the stellar velocity dispersion or bulge luminosity of the host galaxy. Although these correlations remain useful for predicting black-hole masses in less massive elliptical galaxies, our measurements suggest that different evolutionary processes influence the growth of the largest galaxies and their black holes.