CDK2-based CDK7 mimic as a tool for structural analysis: Biochemical validation and crystal structure with SY5609.

Cyclin-dependent kinases (CDKs) regulate cell cycle progression and transcription. CDK7 plays a pivotal role in cell division and proliferation, and the CDK7 gene often exhibits mutations or copy number loss in cancer. Pharmacological targeting of CDK7 has been proposed as a cancer treatment strategy and several inhibitors are currently in clinical trials.

Targeting FMS-like tyrosine kinase 3 (FLT3) in acute myeloid leukemia: Novel molecular approaches and therapeutic challenges.

Acute myeloid leukemia (AML), a heterogeneous hematologic malignancy, has generally a poor prognosis despite the recent advancements in diagnostics and treatment. Genetic instability, particularly mutations in the FMS-like tyrosine kinase 3 (FLT3) gene, is associated with severe outcomes. Approximately 30 % of AML patients harbor FLT3 mutations, which have been linked to higher relapse and reduced survival rates.

Strategies for the treatment of acute myeloid leukemia with FLT3 mutations: a patent review.

Introduction: Approximately one-third of all AML patients have a mutation in the () gene, which is associated with a poor prognosis in these individuals. The 2017 approval of midostaurin, the first FLT3 inhibitor, spurred extensive development of more potent and selective inhibitors with an improved safety profile.

Areas Covered: This review analyzes patent inventions for the treatment of AML using FLT3 inhibitors, covering developments from the earliest to the most recent, disclosed in 2024.

Identification of furo[2,3-d]pyrimidin-4-ylsulfanyl-1,3,4-thiadiazole derivatives as novel FLT3-ITD inhibitors.

Given the significant prevalence of FLT3 receptor and its mutations in acute myeloid leukemia (AML) pathogenesis, we present a novel series of furo[2,3-d]pyrimidin-1,3,4-thiadiazole-urea derivatives, designed to exhibit FLT3-ITD inhibitory activity. These compounds demonstrated cytotoxicity in FLT3-ITD expressing AML cell lines MOLM-13 and MV4-11 in the nanomolar range, with significant selectivity over the K562 cell line. In-depth evaluations of example compound 49 revealed its efficacy in suppressing FLT3 phosphorylation and the downstream signaling molecules, including STAT5 and ERK1/2.

Anticancer dinuclear Ir(III) complex activates Nrf2 and interferes with NAD(H) in cancer cells.

Dinuclear complex [Ir(μ-L1)(η-Cp*)Cl](PF) (1) exhibits low micromolar cytotoxic activity in vitro in various human cancer cells (GI = 1.7-3.0 μM) and outperformed its mononuclear analogue [Ir(η-Cp*)Cl(L2)]PF (2; GI > 40.

Synthesis and photo-induced anticancer activity of new 2-phenylethenyl-1H-benzo[e]indole dyes.

Herein, a series of new 1,1,2-trimethyl-1H-benzo[e]indole dyes was prepared via Knoevenagel condensation reaction between 1,1,2-trimethyl-1H-benzo[e]indole and benzaldehydes, and characterized using various spectroscopic methods. The obtained compounds showed cytotoxic properties in G361 melanoma cell line upon irradiation with 414 nm blue light at submicromolar doses. The mechanism of action of the most potent compound 15 was further investigated.

Synthesis and photodynamic activity of new 5-[(E)-2-(3-alkoxy-1-phenyl-1H-pyrazol-4-yl)ethenyl]-2-phenyl-3H-indoles.

A series of new indole-pyrazole hybrids 8a-m were synthesized through the palladium-catalyzed ligandless Heck coupling reaction from easily accessible unsubstituted, methoxy- or fluoro-substituted 4-ethenyl-1H-pyrazoles and 5-bromo-3H-indoles. These compounds exerted cytotoxicity to melanoma G361 cells when irradiated with blue light (414 nm) and no cytotoxicity in the dark at concentrations up to 10 µM, prompting us to explore their photodynamic effects. The photodynamic properties of the example compound 8d were further investigated in breast cancer MCF-7 cells.

Strategies for overcoming resistance to Bruton's tyrosine kinase inhibitor zanubrutinib.

Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the treatment of B-cell malignancies. They target BTK, a key effector in the B-cell receptor (BCR) signaling pathway, crucial for B-cell survival and proliferation. The first-in-class irreversible BTK inhibitor, ibrutinib, was approved for various B-cell malignancies but has limitations due to off-target effects.

New Inhibitors of Bcr-Abl Based on 2,6,9-Trisubstituted Purine Scaffold Elicit Cytotoxicity in Chronic Myeloid Leukemia-Derived Cell Lines Sensitive and Resistant to TKIs.

Bcr-Abl is an oncoprotein with aberrant tyrosine kinase activity involved in the progression of chronic myeloid leukemia (CML) and has been targeted by inhibitors such as imatinib and nilotinib. However, despite their efficacy in the treatment of CML, a mechanism of resistance to these drugs associated with mutations in the kinase region has emerged. Therefore, in this work, we report the synthesis of 14 new 2,6,9-trisubstituted purines designed from our previous Bcr-Abl inhibitors.

Identification of novel dithiocarbamate-copper complexes targeting p97/NPL4 pathway in cancer cells.

Dithiocarbamates (DTCs) are simple organic compounds with many applications in industry and medicine. They are potent metal chelators forming complexes with various metal ions, including copper. Recently, bis(diethyldithiocarbamate)-copper complex (CuET) has been identified as a metabolic product of the anti-alcoholic drug Antabuse (disulfiram, DSF), standing behind DSF's reported anticancer activity.

Inhibition of FLT3-ITD Kinase in Acute Myeloid Leukemia by New Imidazo[1,2-]pyridazine Derivatives Identified by Scaffold Hopping.

FLT3 kinase is a potential drug target in acute myeloid leukemia (AML). Patients with FLT3 mutations typically have higher relapse rates and worse outcomes than patients without FLT3 mutations. In this study, we investigated the suitability of various heterocycles as central cores of FLT3 inhibitors, including thieno[3,2-]pyrimidine, pyrazolo[1,5-]pyrimidine, imidazo[4,5-]pyridine, pyrido[4,3-]pyrimidine, and imidazo[1,2-]pyridazine.

2,4-Diaryl-pyrimido[1,2-a]benzimidazole derivatives as novel anticancer agents endowed with potent anti-leukemia activity: Synthesis, biological evaluation and kinase profiling.

Acute myeloid leukemia (AML) stands as one of the most aggressive type of human cancer that can develop rapidly and thus requires immediate management. In the current study, the development of novel derivatives of pyrimido[1,2-a]benzimidazole (5a-p) as potential anti-AML agents is reported. The prepared compounds 5a-p were inspected for their in vitro anti-tumor activity at NCI-DTP and subsequently 5h was selected for full panel five-dose screening to assess its TGI, LC and GI values.

A patent review of cyclin-dependent kinase 7 (CDK7) inhibitors (2018-2022).

Introduction: Cyclin-dependent kinase 7 (CDK7) is a member of the CDK family of serine/threonine protein kinases and participates in the regulation of the cell cycle and mRNA transcription. CDK7 is emerging as a possible drug target in oncology and six exciting drug candidates have already undergone early evaluation in clinical trials.

Areas Covered: This review examines CDK7 inhibitors as anticancer drugs reported in patents published in the online databases of the World Intellectual Property Organization and European Patent Office in the 2018-2022 period.

Characterization of new highly selective pyrazolo[4,3-d]pyrimidine inhibitor of CDK7.

Targeting cyclin-dependent kinase 7 (CDK7) provides an interesting therapeutic option in cancer therapy because this kinase participates in regulating the cell cycle and transcription. Here, we describe a new trisubstituted pyrazolo[4,3-d]pyrimidine derivative, LGR6768, that inhibits CDK7 in the nanomolar range and displays favourable selectivity across the CDK family. We determined the structure of fully active CDK2/cyclin A2 in complex with LGR6768 at 2.

Anticancer effect of zanubrutinib in HER2-positive breast cancer cell lines.

Small molecule Bruton's tyrosine kinase (BTK) inhibitors have been developed for the treatment of various haemato-oncological diseases, and ibrutinib was approved as the first BTK inhibitor for anticancer therapy in 2013. Previous reports proved the receptor kinase human epidermal growth factor receptor 2 (HER2) to be a valid off-target kinase of ibrutinib and potentially other irreversible BTK inhibitors, as it possesses a druggable cysteine residue in the active site of the enzyme. These findings suggest ibrutinib as a candidate drug for repositioning in HER2-positive breast cancer (BCa).

Adamantane-Substituted Purine Nucleosides: Synthesis, Host-Guest Complexes with β-Cyclodextrin and Biological Activity.

Purine nucleosides represent an interesting group of nitrogen heterocycles, showing a wide range of biological effects. In this study, we designed and synthesized a series of 6,9-disubstituted and 2,6,9-trisubstituted purine ribonucleosides via consecutive nucleophilic aromatic substitution, glycosylation, and deprotection of the ribofuranose unit. We prepared eight new purine nucleosides bearing unique adamantylated aromatic amines at position 6.

Synthesis and biological activity evaluation of novel 3,5,7-trisubstituted pyrazolo[1,5-a]pyrimidines.

Mutation of FLT3 protein kinase is often associated with deregulated cell proliferation in acute myeloid leukemia and the inhibition of this kinase is a potential therapeutic strategy. We report a novel series of 3,5,7-trisubstituted pyrazolo[1,5-a]pyrimidines prepared in an effort to study their biological activity particularly toward FLT3-ITD and its downstream regulators as well as toward CDK2 and CDK9. Derivative 10b was capable to strongly inhibit all kinases and its selectivity in FLT3-ITD expressing cell lines MOLM13 and MV4-11 was in line with FLT3-ITD inhibition.

Development of fluorescent dual-FRET probe for simultaneous detection of caspase-8 and caspase-9 activities and their relative quantification.

A multi-FRET three-fluorophore probe containing coumarin, fluorescein and rhodamine B with two enzymatically cleavable linkers has been synthesized and optimized for the simultaneous activity detection and relative quantification of two proteases - caspase-8 and caspase-9. The probe designed as a ratiometric single-excitation triple-emission system shows specific change in fluorescence intensities upon enzymatic cleavage of individual linkers in model mixtures as well as in a cell lysate. The activation of caspase-8 and caspase-9 is responsible for initiation of extrinsic or intrinsic apoptotic pathway, respectively, and the probe was proposed as a single chemical tool which could help to decipher a mechanism of cell death induced by various stimuli.

Modulation of FLT3-ITD and CDK9 in acute myeloid leukaemia cells by novel proteolysis targeting chimera (PROTAC).

Oncogenic mutations in gene encoding FLT3 kinase are often detected in acute myeloid leukaemia (AML) patients, and several potent kinase inhibitors have been developed. However, the FLT3 inhibitor treatment often leads to the resistance development and subsequent relapse. Targeted degradation of oncogenic protein kinases has emerged as a feasible pharmacological strategy, providing more robust effect over traditional competitive inhibitors.

Novel effective small-molecule inhibitors of protein kinases related to tau pathology in Alzheimer's disease.

Alzheimer's disease (AD) drugs in therapy are limited to acetylcholine esterase inhibitors and memantine. Newly developed drugs against a single target structure have an insufficient effect on symptomatic AD patients. Novel aromatically anellated pyridofuranes have been evaluated for inhibition of AD-relevant protein kinases cdk1, cdk2, gsk-3b and Fyn.

3,5,7-Substituted Pyrazolo[4,3-]Pyrimidine Inhibitors of Cyclin-Dependent Kinases and Cyclin K Degraders.

3,5,7-Trisubstituted pyrazolo[4,3-]pyrimidines have been identified as potent inhibitors of cyclin-dependent kinases (CDKs), which are established drug targets. Herein, we describe their further structural modifications leading to novel nanomolar inhibitors with strong antiproliferative activity. We determined the crystal structure of fully active CDK2/A2 with 5-(2-amino-1-ethyl)thio-3-cyclobutyl-7-[4-(pyrazol-1-yl)benzyl]amino-1(2)-pyrazolo[4,3-]pyrimidine () at 1.

Design, Synthesis, In Silico Studies and Inhibitory Activity towards Bcr-Abl, BTK and FLT3-ITD of New 2,6,9-Trisubstituted Purine Derivatives as Potential Agents for the Treatment of Leukaemia.

We report 31 new compounds designed, synthesized and evaluated on Bcr-Abl, BTK and FLT3-ITD as part of our program to develop 2,6,9-trisubstituted purine derivatives as inhibitors of oncogenic kinases. The design was inspired by the chemical structures of well-known kinase inhibitors and our previously developed purine derivatives. The synthesis of these purines was simple and used a microwave reactor for the final step.