KF1601, a dual inhibitor of BCR::ABL1 and FLT3, overcomes drug resistance in FLT3 blast phase chronic myeloid leukemia.

Blast phase chronic myeloid leukemia (BP-CML) poses significant clinical challenges due to its drug resistance, resulting from BCR::ABL1-dependent mutations and BCR::ABL1-independent pathways. Previously, we reported that FLT3 pathway is activated in ~ 50% of BP-CML cases, indicating a potential avenue for therapeutic intervention via dual inhibition of BCR::ABL1 and FLT3. Here, we aimed to evaluate the efficacy of KF1601, a dual inhibitor of BCR::ABL1 and FLT3, in overcoming drug resistance in BP-CML while also comparing its thrombo-inflammatory responses with those of ponatinib, known to have severe cardiovascular adverse events in human.

Extremely durable electrical impedance tomography-based soft and ultrathin wearable e-skin for three-dimensional tactile interfaces.

In the rapidly evolving field of human-machine interfaces (HMIs), high-resolution wearable electronic skin (e-skin) is essential for user interaction. However, traditional array-structured tactile interfaces require increased number of interconnects, while soft material-based computational methods have limited functionalities. Here, we introduce a thin and soft e-skin for tactile interfaces, offering high mapping capabilities through electrical impedance tomography (EIT).

Stimulatory Effects of KPR-A148 on Osteoblast Differentiation and Bone Regeneration.

Background: Xanthine derivatives have been used to treat a variety of medical conditions including respiratory disease and neural degeneration. However, few studies have reported their effects on bone regeneration. Therefore, we investigated the effects of KPR-A148, a synthetic xanthine derivative on osteoblast differentiation and bone regeneration .

Inhibitory Effect of KP-A038 on Osteoclastogenesis and Inflammatory Bone Loss Is Associated With Downregulation of Blimp1.

Excessive osteoclastic activity results in pathological bone resorptive diseases, such as osteoporosis, periodontitis, and rheumatoid arthritis. As imidazole-containing compounds possess extensive therapeutic potential for the management of diverse diseases, we synthesized a series of imidazole derivatives and investigated their effects on osteoclast differentiation and function. In the present study, we found that a novel imidazole derivative, KP-A038, suppressed receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclastogenesis and bone-resorbing activity and attenuated lipopolysaccharide (LPS)-induced bone destruction .

Identification of LEM-14 inhibitor of the oncoprotein NSD2.

The NSD family (NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1) are histone lysine methyltransferases (HMTases) essential for chromatin regulation. The NSDs are oncoproteins, drivers of a number of tumors and are considered important drug-targets but the lack of potent and selective inhibitors hampers further therapeutic development and limits exploration of their biology. In particular, MMSET/NSD2 selective inhibition is being pursued for therapeutic interventions against multiple myeloma (MM) cases, especially in multiple myeloma t(4;14)(p16.

Characterization of CYPs and UGTs Involved in Human Liver Microsomal Metabolism of Osthenol.

Osthenol is a prenylated coumarin isolated from the root of and , and is an -demethylated metabolite of osthole in vivo. Its various pharmacological effects have been reported previously. The metabolic pathway of osthenol was partially confirmed in rat osthole studies, and 11 metabolic products were identified in rat urine.

A novel benzamide derivative protects ligature-induced alveolar bone erosion by inhibiting NFATc1-mediated osteoclastogenesis.

Since elevated osteoclast formation and/or activity by inhibitory responses against pathogens leads to diverse osteolytic bone diseases including periodontitis, inhibition of osteoclast differentiation and bone resorption has been a primary therapeutic strategy. In this study, we investigated the therapeutic potential of a novel benzamide-linked molecule, OCLI-070, for preventing alveolar bone loss in mice with ligature-induced experimental periodontitis. OCLI-070 inhibited osteoclast formation by acting on both early and late stages of differentiation, and attenuated the induction of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) and the expression of osteoclast-specific genes.

Characterization of in vitro and in vivo metabolism of leelamine using liquid chromatography-tandem mass spectrometry.

Leelamine is a diterpene compound found in the bark of pine trees and has garnered considerable interest owing to its potent anticancer properties. The aim of the present study was to investigate the metabolic profile of leelamine in human liver microsomes (HLMs) and mice using liquid chromatography-tandem mass spectrometry (LC-MS/MS). We found that leelamine undergoes only Phase I metabolism, which generates one metabolite that is mono-hydroxylated at the C9 carbon of the octahydrophenanthrene ring (M1) both in vitro and in vivo.

Isolation, Synthesis, and Antisepsis Effects of a C-Methylcoumarinochromone Isolated from Abronia nana Cell Culture.

Only a few isoflavones have been isolated from plants of the genus Abronia. The biological properties of compounds isolated from Abronia species have not been well established, and their antisepsis effects have not been reported yet. In the present study, a new C-methylcoumarinochromone, was isolated from Abronia nana suspension cultures.

OCLI-023, a Novel Pyrimidine Compound, Suppresses Osteoclastogenesis In Vitro and Alveolar Bone Resorption In Vivo.

An abnormal increase in osteoclast differentiation and activation results in various bone-resorptive diseases, including periodontitis, rheumatoid arthritis, and osteoporosis. Chemical compounds containing pyrimidine ring have been shown to regulate a variety of biological processes. Therefore, in order to identify an antiresorptive agent, we synthesized a series of pyrimidine ring-containing chemical compounds, and found that OCLI-023 suppressed the differentiation and activation of osteoclasts in vitro.

Molecular and functional evaluation of a novel HIF inhibitor, benzopyranyl 1,2,3-triazole compound.

Hypoxia occurs in a variety of pathological events, including the formation of solid tumors. Hypoxia-inducible factor (HIF)-1α is stabilized under hypoxic conditions and is a key molecule in tumor growth and angiogenesis. Seeking to develop novel cancer therapeutics, we investigated small molecules from our in-house chemical libraries to target HIF-1α.

Lipidomic platform for structural identification of skin ceramides with α-hydroxyacyl chains.

Skin ceramides are sphingolipids consisting of sphingoid bases, which are linked to fatty acids via an amide bond. Typical fatty acid acyl chains are composed of α-hydroxy fatty acid (A), esterified ω-hydroxy fatty acid (EO), non-hydroxy fatty acid (N), and ω-hydroxy fatty acid (O). We recently established a lipidomic platform to identify skin ceramides with non-hydroxyacyl chains using tandem mass spectrometry.

Solid-Phase Synthesis of 1,3,7,8-Tetrasubstituted Xanthine Derivatives on Traceless Solid Support.

Traceless solid-phase synthesis of 1,3,7,8-tetrasubstituted xanthine (1,3,7,8-tetrasubstituted 1H-purine-2,6(3H,7H)-dione) derivatives has been developed. The solid-phase synthetic route began on a solid supported N'-cyano-N-substituted carbamimidothioate, which was prepared from cyanamide, isothiocyanate, and Merrifield resin. After N-alkylation of carbamimidothioate resin with ethyl 2-bromoacetate, an imidazole ring is introduced by Thorpe-Ziegler-type cyclization.

Efficient Syntheses of 1,2,3-Triazoloamide Derivatives Using Solid- and Solution-Phase Synthetic Approaches.

Efficient synthetic routes for the preparation of secondary and tertiary 1,2,3-triazoloamide derivatives were developed. A secondary α-1,2,3-triazoloamide library was constructed and expanded by a previously developed solid-phase synthetic route and a tertiary 1,2,3-triazoloamide library was constructed by a parallel solution-phase synthetic route. The synthetic routes rely on amide formation with secondary amines and chloro-acid chlorides; SN2 reaction with sodium azide; and the selective [3 + 2] Hüisgen cycloaddition with appropriate terminal alkynes.

Inhibitory Effects of KP-A159, a Thiazolopyridine Derivative, on Osteoclast Differentiation, Function, and Inflammatory Bone Loss via Suppression of RANKL-Induced MAP Kinase Signaling Pathway.

Abnormally elevated formation and activation of osteoclasts are primary causes for a majority of skeletal diseases. In this study, we found that KP-A159, a newly synthesized thiazolopyridine derivative, inhibited osteoclast differentiation and function in vitro, and inflammatory bone loss in vivo. KP-A159 did not cause a cytotoxic response in bone marrow macrophages (BMMs), but significantly inhibited the formation of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts induced by macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL).

The 1,2,3-triazole derivative KP-A021 suppresses osteoclast differentiation and function by inhibiting RANKL-mediated MEK-ERK signaling pathway.

The triazole family of compounds has been implicated in modulating various biological processes such as inflammation, tumorigenesis, and infection. To our knowledge, this is the first study to demonstrate the effects of 1,2,3-triazole substituted biarylacrylonitrile compounds, including KP-A021, on the differentiation and function of osteoclasts. KP-A021 and its triazole derivatives, at a concentration that does not cause a cytotoxic response in bone marrow macrophages (BMMs), significantly inhibited osteoclast differentiation induced by receptor activator of nuclear factor-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) as assessed by tartrate-resistant acid phosphatase (TRAP) staining.

Serendipitous discovery of 2-((phenylsulfonyl)methyl)-thieno[3,2-d]pyrimidine derivatives as novel HIV-1 replication inhibitors.

We identified a novel class of 2-((phenylsulfonyl)methyl)-thieno[3,2-d]pyrimidine compounds as potent HIV-1 replication inhibitors serendipitously during the process of evaluation of triazolothienopyrimidine (TTPM) compounds. Herein, we report synthesis and biological evaluation of 2-((phenylsulfonyl)methyl)-thieno[3,2-d]pyrimidine compounds using a cell-based full replication assay to identify thienopyrimidines 6 and 30, which could be further utilized as viable lead compounds.

Selective induction of hepatic cytochrome P450 2B activity by leelamine in vivo, as a potent novel inducer.

Cytochrome P450 (CYP) is an important enzyme that can act on xenobiotic substances such as toxic chemicals or drugs. Phenobarbital (PB) has been widely used to induce CYP2B activity to investigate the drug-drug interaction of CYP2B substrate drugs. Leelamine is a diterpene compound, and is the current focus of efforts to develop a treatment for diabetes.

A derivative of imidazobenzimidazole, ML106, inhibits melanin synthesis via p38 MAPK activation.

We investigated the effects of ML106 on melanogenesis in B16F10 melanoma cells. Our results showed that ML106 decreased melanin content and tyrosinase activity in a dose-dependent manner. Interestingly, ML106 did not inhibit microphthalmia-associated transcription factor (MITF) expression, but did decrease tyrosinase expression.

Identification of metabolites of N-(5-benzoyl-2-(4-(2-methoxyphenyl)piperazin-1-yl)thiazol-4-yl)pivalamide including CYP3A4-mediated C-demethylation in human liver microsomes with high-resolution/high-accuracy tandem mass.

KRO-105714 [N-(5-benzoyl-2-(4-(2-methoxyphenyl)piperazin-1-yl)thiazol-4-yl)pivalamide] is a 2,4,5-trisubstituted 1,3-thiazole derivative that exerts anti-atopic dermatitis activity via robust suppression of the sphingosylphosphorylcholine receptor. This study used high-resolution/high-accuracy tandem mass spectroscopy (HRMS) and recombinant cDNA-expressed cytochrome P450 (P450) isoforms to identify the metabolic pathway and metabolites of KRO-105714 in human liver microsomes (HLMs) as therapeutic agents for inflammation. The incubation of KRO-105714 with pooled HLMs in the presence of NADPH generated four metabolites (M1-M4).

Emodin-6-O-β-D--glucoside inhibits high-glucose-induced vascular inflammation.

Emodin-6-O-β-D-glucoside (EG), a new active compound from Reynoutria japonica, has recently been shown to exert potent anti-inflammatory and barrier protective effects in human umbilical vein endothelial cells (HUVECs) and in mice. Vascular inflammatory process has been suggested to play a key role in initiation and progression of atherosclerosis, a major complication of diabetes mellitus. Thus, we attempted to determine whether EG can suppress the vascular inflammatory process induced by high glucose (HG) in HUVECs and mice.

CYP2J2 and CYP2C19 are the major enzymes responsible for metabolism of albendazole and fenbendazole in human liver microsomes and recombinant P450 assay systems.

Albendazole and fenbendazole are broad-spectrum anthelmintics that undergo extensive metabolism to form hydroxyl and sulfoxide metabolites. Although CYP3A and flavin-containing monooxygenase have been implicated in sulfoxide metabolite formation, the enzymes responsible for hydroxyl metabolite formation have not been identified. In this study, we used human liver microsomes and recombinant cytochrome P450s (P450s) to characterize the enzymes involved in the formation of hydroxyalbendazole and hydroxyfenbendazole from albendazole and fenbendazole, respectively.

Determination of leelamine in mouse plasma by LC-MS/MS and its pharmacokinetics.

Leelamine may be applicable to treat diabetes and is known to inhibit pyruvate dehydrogenase kinase 4. In this study, we developed and validated a quantification method using liquid chromatography (LC) coupled with tandem mass spectrometry analysis, which was applied to a pharmacokinetic investigation in mouse plasma. Leelamine transition ions in multiple reaction-monitoring modes using positive ionization were observed at m/z 286.

In vitro metabolism of obovatol and its effect on cytochrome P450 enzyme activities in human liver microsomes.

Obovatol, a major constituent of the leaves of Magnolia obovata Thunb, is known to inhibit nuclear factor-κB activity and arachidonic acid-induced platelet aggregation. This study was performed to identify the metabolites of obovatol in human liver microsomes. Human liver microsomes incubated with obovatol in the presence of NADPH and/or UDPGA resulted in the formation of six metabolites, M1-M6.

Synthesis and biological evaluation of triazolothienopyrimidine derivatives as novel HIV-1 replication inhibitors.

We identified a novel class of triazolothienopyrimidine (TTPM) compounds as potent HIV-1 replication inhibitors during a high-throughput screening campaign that evaluated more than 200,000 compounds using a cell-based full replication assay. Herein, we report the optimization of the antiviral activity in a cell-based assay system leading to the discovery of aryl-substituted TTPM derivatives (38, 44, and 45), which exhibited significant inhibition of HIV-1 replication with acceptable safety margins. These novel and potent TTPMs could serve as leads for further development.