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

Insights into Current Tropomyosin Receptor Kinase (TRK) inhibitors: development and clinical application

The use of kinase-directed precision medicine has been heavily pursued since the discovery and development of imatinib. Annually, it is estimated that around ∼20 000 new cases of tropomyosin receptor kinase (TRK) cancers are diagnosed, with the majority of cases exhibiting a TRK genomic rearrangement. In this Perspective, we discuss current development and clinical applications for TRK precision medicine by providing the following: (1) the biological background and significance of the TRK kinase family, (2) a compilation of known TRK inhibitors and analysis of their cocrystal structures, (3) an overview of TRK clinical trials, and (4) future perspectives for drug discovery and development of TRK inhibitors

Discovery and Development of Novel Ret Inhibitors for the Treatment of Pervasive Malignancies

Targeted cancer therapeutics represent the advent of a new therapeutic age, brought forth by the small molecule tyrosine kinase inhibitor (TKI) imatinib (Gleevec®). Imatinib is able to cause complete and sustained remissions in patients with chronic myelogenous leukemia (CML) driven by the Abelson (ABL) kinase, which caused a massive paradigm shift in how cancer is treated. The following research has been completed to extend the principles of imatinib therapy to the rearranged during transfection (RET) kinase. The RET kinase is involved in driving the pathology of medullary thyroid cancer (MTC), papillary thyroid carcinoma (PTC), certain non-small cell lung cancers (NSCLC), chronic myelomonocytic leukemia (CMML), tamoxifen resistant breast cancer, and Spitz melanoma. A heavily diverse population of solid and liquid carcinomas are driven by the RET oncogene, and patients presenting with these cancers could significantly benefit from a RET inhibitor. Previous drug discovery campaigns identified RET activity after therapeutic development for an unrelated kinase, as the case with vandetanib (Calpresa®) and cabozantinib (Cometriq®). Both agents fail to achieve dominant activity on RET and are more active on the vascular endothelial growth factor receptor 2 (VEGFR2), yet still achieve efficacy in RET driven tumors. This likely results from interrupting the oncogene cooperation between RET and VEGFR2; VEGFR2 provides the nutrients through angiogenesis that RET requires to promote proliferation and survival. We hypothesized that an equipotent RET/VEGFR2 dual inhibitor could maximize inhibiting the cooperation between RET and VEGFR2 in RET driven cancers. The inhibitor should be developed to maintain activity on all known RET mutations for treatment durability. In that case, the RET oncogene, despite mutating, will always be inhibited. Through research efforts, Pz-1 was identified as a sub-nanomolar, equipotent inhibitor of both RET (IC₅₀<0.001 µM) and VEGFR2 (IC₅₀<0.001 µM). Pz-1 was found active on every known, clinically relevant RET mutant tested at an IC₅₀≤0.001 µM. Through RET-driven xenograft models, Pz-1 was found active at an oral dose as low as 0.3 mg/kg/day.Release 23-Jun-201

(Z)-N-tert-Butyl-2-(4-methoxyanilino)-N&#8242;-(4-methoxyphenyl)-2-phenylacetimidamide

In the crystal of the title compound, C26H31N3O2, pairs of N&#8212;H...O hydrogen bonds link molecules, forming inversion dimers, which enclose an R22(20) ring motif. One N atom does not form hydrogen bonds and lies in a hydrophobic pocket with closest intermolecular contacts of 4.196&#8197;(2) and 4.262&#8197;(2)&#8197;&#197;

Efficient Access to 2,3-Diarylimidazo[1,2‑<i>a</i>]pyridines via a One-Pot, Ligand-Free, Palladium-Catalyzed Three-Component Reaction under Microwave Irradiation

An expeditious one-pot, ligand-free, Pd­(OAc)₂-catalyzed, three-component reaction for the synthesis of 2,3-diarylimidazo­[1,2-<i>a</i>]­pyridines was developed under microwave irradiation. With the high availability of commercial reagents and great efficiency in expanding molecule diversity, this methodology is superior to the existing procedures for the synthesis of 2,3-diarylimidazo­[1,2-<i>a</i>]­pyridines analogues

Computer aided drug discovery of highly ligand efficient, low molecular weight imidazopyridine analogs as FLT3 inhibitors

The FLT3 kinase represents an attractive target to effectively treat AML. Unfortunately, no FLT3 targeted therapeutic is currently approved. In line with our continued interests in treating kinase related disease for anti-FLT3 mutant activity, we utilized pioneering synthetic methodology in combination with computer aided drug discovery and identified low molecular weight, highly ligand efficient, FLT3 kinase inhibitors. Compounds were analyzed for biochemical inhibition, their ability to selectively inhibit cell proliferation, for FLT3 mutant activity, and preliminary aqueous solubility. Validated hits were discovered that can serve as starting platforms for lead candidates

Targeting a Novel G-Quadruplex in the <i>CARD11</i> Oncogene Promoter with Naptho(2,1-b)furan-1-ethanol,2-nitro- Requires the Nitro Group

The aggressive nature of the activated B cell such as (ABC) subtype of diffuse large B cell (DLBCL) is frequently associated with altered B cell Receptor (BCR) signaling through the activation of key components including the scaffolding protein, CARD11. Most inhibitors, such as ibrutinib, target downstream BCR kinases with often modest and temporary responses for DLBCL patients. Here, we pursue an alternative strategy to target the BCR pathway by leveraging a novel DNA secondary structure to repress transcription. We discovered that a highly guanine (G)-rich element within the CARD11 promoter forms a stable G-quadruplex (G4) using circular dichroism and polymerase stop biophysical techniques. We then identified a small molecule, naptho(2,1-b)furan-1-ethanol,2-nitro- (NSC373981), from a fluorescence-resonance energy transfer-based screen that stabilized CARD11 G4 and inhibited CARD11 transcription in DLBCL cells. In generating and testing analogs of NSC373981, we determined that the nitro group is likely essential for the downregulation of CARD11 and interaction with CARD11 G4, and the removal of the ethanol side chain enhanced this activity. Of note, the expression of BCL2 and MYC, two other key oncogenes in DLBCL pathology with known promoter G4 structures, were often concurrently repressed with NSC373981 and the highly potent R158 analog. Our findings highlight a novel approach to treat aggressive DLBCL by silencing CARD11 gene expression that warrants further investigation