The causal relationship between serum metabolites and acne vulgaris: a Mendelian randomization study.

In individuals with acne vulgaris, alterations occur in serum metabolite composition, yet the exact causal link between these metabolites and acne development remains elusive. Using genome-wide association datasets, we performed bidirectional Mendelian randomization (MR) to investigate the potential causal relationship between 309 serum metabolites and acne vulgaris. We performed sensitivity analysis to evaluate the presence of heterogeneity and pleiotropy. Forward MR analysis found 14 serum metabolites significantly associated with acne vulgaris, and reverse MR analysis found no significant association between acne vulgaris and these serum metabolites. Through validation using data from the FinnGen database of acne vulgaris studies, we found a conclusive and significant correlation between stearoylcarnitine and acne vulgaris. This provides new evidence in the search for new targets for the treatment of acne vulgaris.

Discovery of 2H-benzo[b][1,4]oxazin-3(4H)-one derivatives as potent and selective CDK9 inhibitors that enable transient target engagement for the treatment of hematologic malignancies.

Cyclin-dependent kinase 9 (CDK9) is a transcriptional regulator and a potential therapeutic target in hematologic malignancies. Selective and transient CDK9 inhibition reduces Mcl-1 expression and induces apoptosis in Mcl-1-dependent tumor cells for survival. Here, we describe our efforts to discover a novel series of 2H-benzo[b][1,4]oxazin-3(4H)-one as CDK9 inhibitors. Compound 32k was identified as a selective CDK9 inhibitor with short pharmacokinetic and physicochemical properties suitable for intravenous administration. Short-term treatment with 32k resulted in a rapid dose-dependent decrease in cellular p-Ser2-RNAPII, Mcl-1 and c-Myc, leading to apoptosis in the MV4-11 cell line. Correspondingly, significant in vivo antitumor efficacy was observed in xenograft models derived from multiple hematological tumors with intermittent 32k dosing. These results provide evidence that selective transient CDK9 inhibitors could be used for the treatment of hematologic malignancies.

Discovery of N-(4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)-4-(4-methylpiperazin-1-yl)quinazolin-7-amine as a Novel, Potent, and Oral Cyclin-Dependent Kinase Inhibitor against Haematological Malignancies.

Hematologic malignancies (HM) start in blood forming tissue or in the cells of the immune system. Cyclin-dependent kinases (CDKs) regulate cell cycle progression, and some of them control cellular transcription. CDK inhibition can trigger apoptosis and could be particularly useful in hematological malignancies. Herein, we describe our efforts toward the discovery of a novel series of quinazoline derivatives as CDK inhibitors. Intensive structural modifications lead to the identification of compound 37d as the most active inhibitors of CDKs 1, 2, 4, 8 and 9 with balancing potency and selectivity against CDKs. Further biological studies revealed that compound 37d can arrest the cell cycle and induce apoptosis via activating PARP and caspase 3. More importantly, compound 37d showed good antitumor efficacy in multiple HM mice xenograft models with no obvious toxicity. These results indicated that CDK 1, 2, 4, 8, and 9 inhibitors could be potentially used to treat certain hematologic malignancies.

The discovery of quinoline derivatives, as NF-κB inducing kinase (NIK) inhibitors with anti-inflammatory effects in vitro, low toxicities against T cell growth.

NIK is a critical regulatory protein of the non-classical NF-kB pathway, and its dysregulated activation has been proved to be one of the pathogenic factors in a variety of autoimmune diseases and inflammatory diseases. Nevertheless, its corresponding development of inhibitors faces many obstacles, including the lack of structure types of known inhibitors, immature activity evaluation methods of compounds in vitro. In this study, a series of quinoline derivatives were obtained through rational design and chemical synthesis. Among them, the representative compounds 17c and 24c have excellent inhibitory activities on LPS-induced macrophage (J774) nitric oxide release and anti-Con A-stimulated primary T cell proliferation. This evaluation method has good universality and overcomes the obstacles mentioned above, which are faced by the current inhibitor research to a certain extent. Besides, the compound's toxicity against the growth of T cells under non-stress conditions was evaluated, for the first time, as an indicator for the investigation to avoid potential safety risks. Pharmacokinetic properties evaluation of the less toxic compound 24c confirmed its good metabolic behavior (especially oral properties, F% = 21.7%), and subsequent development value.

Identification of N-Phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine Derivatives as Novel, Potent, and Selective NF-κB Inducing Kinase (NIK) Inhibitors for the Treatment of Psoriasis.

A series of N-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine derivatives with NF-κB inducing kinase (NIK) inhibitory activity were obtained through structure-based drug design and synthetic chemistry. Among them, 4-(3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4-morpholinophenyl)-2-(thiazol-2-yl)but-3-yn-2-ol (12f) was identified as a highly potent NIK inhibitor, along with satisfactory selectivity. The pharmacokinetics of 12f and its ability to inhibit interleukin 6 secretion in BEAS-2B cells were better than compound 1 developed by Amgen. Oral administration of different doses of 12f in an imiquimod-induced psoriasis mouse model showed effective alleviation of psoriasis, including invasive erythema, swelling, skin thickening, and scales. The underlying pathological mechanism involved attenuation of proinflammatory cytokine and chemokine gene expression, and the infiltration of macrophages after the treatment of 12f. This work provides a foundation for the development of NIK inhibitors, highlighting the potential of developing NIK inhibitors as a new strategy for the treatment of psoriasis.

Discovery of coumarin derivatives as potent and selective cyclin-dependent kinase 9 (CDK9) inhibitors with high antitumour activity.

Specific inhibition of CDK9 is considered a promising strategy for developing effective anticancer therapeutics. However, most of the reported CDK9 inhibitors are still at an early stage of development and lack selectivity against other CDKs. Herein, we discovered coumarin derivative 30i as a potent CDK9 inhibitor with high selectivity (8300-fold over CDK7). Binding mode analysis illustrated that the substituent coumarin moiety is a critical group for CDK9 selectivity by occupying a flexible hinge/αD region, which is sterically hindered in other CDKs. Compound 30i showed excellent cellular antiproliferative activity, moderate pharmacokinetic property and low hERG inhibition. Moreover, 30i significantly induced tumour growth inhibition in a dose-dependent manner without causing an obvious loss of body weight in an MV4-11 xenograft mice model. Altogether, these results suggest that 30i may serve as a potential acute myeloid leukaemia (AML) therapeutics by selectively targeting CDK9.

Optimized dyeing conditions of immunoprotein with reactive dye Procion Blue MX-7RX.

For investigating the feasibility of using reactive dyes as an immunoassay marker, a dichlorine triazine dye, Procion Blue MX-7RX, was employed to stain the antibody against human serum albumin (anti-HSA). With the color intensity revealed in the immunochromatographic test strip as the objective variables, the optimal dyeing conditions were found as follows: pH 11.4, temperature 35.7 degrees C, molar ratio 188 (mol dye/mol antibody), and reaction time 45.6 min. The dyed-anti-HSA revealed a maximal color intensity of 8738 without apparent loss of antigen binding affinity.