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The retinoic acid receptor-related orphan receptor γt (RORγt) is a key regulator of Th17 cells, associated with autoimmune diseases, making it a significant drug target. Herein, we designed and synthesized 1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline derivatives, improving upon GSK2981278 to enhance bioavailability. Of which, D4 exhibited superior bioavailability (F = 48.1 and 32.9% in mice and rats, respectively) compared to GSK2981278 (F = 6.2 and 4.1%, respectively), and effectively treated psoriasis in mice at lower doses. Moreover, for the first time, we report the efficacies of a RORγt inverse agonist in mouse models of rheumatoid arthritis. ( R )-D4 , the eutomer of D4 , matched or exceeded GSK2981278's therapeutic effects at lower doses, with no adverse effects observed after 2 weeks of administration. These results position ( R )-D4 as a promising and orally bioavailable candidate for Th17-mediated autoimmune disease treatment.

The aim of this study was to reveal the effects of yeast culture replacing fish meal (FM) or chicken meal (CM) on the growth performance, serum biochemical indexes, intestinal digestive enzyme activities, hepatic antioxidant, and hepatic and intestinal histology of bullfrog ( Lithobates catesbeianus ). The basal diet contained 100 g/kg FM and 100 g/kg CM, and then yeast culture was used to decrease FM or CM level to 75 and 50 g/kg with yeast culture inclusion of 32 and 64 g/kg, respectively, resulting in five groups of isonitrogenous diets (control, FM75, FM50, CM75, and CM50). A total of 450 bullfrogs (45.5 ± 0.4 g initial weight) were fed the five diets for 50 days. (1) The FM50 group presented significantly lower weight gain, condition factor, hind leg index, and higher feed conversion ratio than the control group, while the other three groups of FM75, CM75, and CM50 showed no significant difference in growth performance when compared to the control group. (2) The serum triglyceride content of FM50 group was significantly lower, while the alkaline phosphatase activity was significantly higher than those of the control group. The serum total cholesterol levels were significantly lower in the CM50 group compared to the control group. (3) In intestinal digestive enzyme activities, the trypsin and α-amylase activities in the CM75 and CM50 groups, the trypsin activity in the FM75 group, and lipase activity in the CM50 group were all significantly higher than those in the other groups. (4) The replacement of 50% FM with yeast culture (FM50 and CM50 groups) promoted the total antioxidant capacity in the liver, but compared to the control group, the intestinal villi height and muscularis propria thickness in the FM50 group were significantly lower. There was no difference ( P > 0.05) in liver histology among all the groups. In conclusion, in a basal diet containing 100 g/kg FM and 100 g/kg CM, 32.0 and 64.0 g/kg yeast cultures could successfully replace 25% of dietary FM and 50% of dietary CM without negative effects on the growth performance, serum biochemical indexes, and hepatic and intestinal health of bullfrogs., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Yun-Feng Chen et al.)

The FLT3-ITD (internal tandem duplication) mutant has been a promising target for acute myeloid leukemia (AML) drug discovery but is now facing the challenge of resistance due to point mutations. Herein, we have discovered a type II FLT3 inhibitor, SILA-123 . This inhibitor has shown highly potent inhibitory effects against FLT3-WT (IC 50 = 2.1 nM) and FLT3-ITD (IC 50 = 1.0 nM), tumor cells with the FLT3-ITD mutant such as MOLM-13 (IC 50 = 0.98 nM) and MV4-11 (IC 50 = 0.19 nM), as well as BaF3 cells associated with the FLT3-ITD mutant and point mutations like BaF3-FLT3-ITD-G697R (IC 50 = 3.0 nM). Moreover, SILA-123 exhibited promising kinome selectivity against 310 kinases (S score (10) = 0.06). In in vivo studies, SILA-123 significantly suppressed the tumor growth in MV4-11 (50 mg/kg/d, TGI = 87.3%) and BaF3-FLT3-ITD-G697R (50 mg/kg/d, TGI = 60.0%) cell-inoculated allograft models. Our data suggested that SILA-123 might be a promising drug candidate for FLT3-ITD-positive AML.

Kinases, a class of enzymes controlling various substrates phosphorylation, are pivotal in both physiological and pathological processes. Although their conserved ATP binding pockets pose challenges for achieving selectivity, this feature offers opportunities for drug repositioning of kinase inhibitors (KIs). This study presents a cost-effective in silico prediction of KIs drug repositioning via analyzing cross-docking results. We established the KIs database (278 unique KIs, 1834 bioactivity data points) and kinases database (357 kinase structures categorized by the DFG motif) for carrying out cross-docking. Comparative analysis of the docking scores and reported experimental bioactivity revealed that the Atypical, TK, and TKL superfamilies are suitable for drug repositioning. Among these kinase superfamilies, Olverematinib, Lapatinib, and Abemaciclib displayed enzymatic activity in our focused AKT-PI3K-mTOR pathway with IC 50 values of 3.3, 3.2 and 5.8 μM. Further cell assays showed IC 50 values of 0.2, 1.2 and 0.6 μM in tumor cells. The consistent result between prediction and validation demonstrated that repositioning KIs via in silico method is feasible., (© 2024 Wiley-VCH GmbH.)

Multiple myeloma (MM), a cancer of plasma cells, is the second most common hematological malignancy which is characterized by aberrant plasma cells infiltration in the bone marrow and complex heterogeneous cytogenetic abnormalities. Over the past two decades, novel treatment strategies such as proteasome inhibitors, immunomodulators, and monoclonal antibodies have significantly improved the relative survival rate of MM patients. However, the development of drug resistance results in the majority of MM patients suffering from relapse, limited treatment options and uncontrolled disease progression after relapse. There are urgent needs to develop and explore novel MM treatment strategies to overcome drug resistance and improve efficacy. Here, we review the recent small molecule therapeutic strategies for MM, and introduce potential new targets and corresponding modulators in detail. In addition, this paper also summarizes the progress of multi-target inhibitor therapy and protein degradation technology in the treatment of MM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Over the past decades, the role of rearranged during transfection (RET) alterations in tumorigenesis has been firmly established. RET kinase inhibition is an essential therapeutic target in patients with RET-altered cancers. In clinical practice, initial efficacy can be achieved in patients through the utilization of multikinase inhibitors (MKIs) with RET inhibitory activity. However, the effectiveness of these MKIs is impeded by the adverse events associated with off-target effects. Recently, many RET-selective inhibitors, characterized by heightened specificity and potency, have been developed, representing a substantial breakthrough in the field of RET precision oncology. This Perspective focuses on the contemporary understanding of RET mutations, recent advancements in next-generation RET inhibitors, and the challenges associated with resistance to RET inhibitors. It provides valuable insights for the development of next-generation MKIs and selective RET inhibitors.

Acute myeloid leukemia (AML) is the most common type of blood cancer and has been strongly correlated with the overexpression of Fms-like tyrosine kinase 3 (FLT3), a member of the class III receptor tyrosine kinase family. With the emergence of FLT3 internal tandem duplication alteration (ITD) and tyrosine kinase domain (TKD) mutations, the development of FLT3 small molecule inhibitors has become an effective medicinal chemistry strategy for AML. Herein, we have designed and synthesized two series of 1H-pyrrolo[2,3-b]pyridine derivatives CM1-CM24, as FLT3 inhibitors based on F14, which we previously reported, that can target the hydrophobic FLT3 back pocket. Among these derivates, CM5 showed significant inhibition of FLT3 and FLT3-ITD, with inhibitory percentages of 57.72 % and 53.77 % respectively at the concentration of 1 μΜ. Furthermore, CM5 demonstrated potent inhibition against FLT3-dependent human AML cell lines MOLM-13 and MV4-11 (both harboring FLT3-ITD mutant), with IC 50 values of 0.75 μM and 0.64 μM respectively. In our cellular mechanistic studies, CM5 also effectively induces apoptosis by arresting cell cycle progression in the G0/G1 phase. In addition, the amide and urea linker function were discussed in detail based on computational simulations studies. CM5 will serve as a novel lead compound for further structural modification and development of FLT3 inhibitors specifically targeting AML with FLT3-ITD mutations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)