Preclinical Evaluation of JAB-2485, a Potent AURKA Inhibitor with High Selectivity and Favorable Pharmacokinetic Properties.

As a critical mitotic regulator, Aurora kinase A (AURKA) is aberrantly activated in a wide range of cancers. Therapeutic targeting of AUKRA is a promising strategy for the treatment of solid tumors. In this study, we evaluated the preclinical characteristics of JAB-2485, a small-molecule inhibitor of AURKA currently in Phase I/IIa clinical trial in the US (NCT05490472). Biochemical studies demonstrated that JAB-2485 is potent and highly selective on AURKA, with subnanomolar IC50 and around 1500-fold selectivity over AURKB or AURKC. In addition, JAB-2485 exhibited favorable pharmacokinetic properties featured by low clearance and good bioavailability, strong dose-response relationship, as well as low risk for hematotoxicity and off-target liability. As a single agent, JAB-2485 effectively induced G2/M cell cycle arrest and apoptosis and inhibited the proliferation of small cell lung cancer, triple-negative breast cancer, and neuroblastoma cells. Furthermore, JAB-2485 exhibited robust in vivo antitumor activity both as monotherapy and in combination with chemotherapies or the bromodomain inhibitor JAB-8263 in xenograft models of various cancer types. Together, these encouraging preclinical data provide a strong basis for safety and efficacy evaluations of JAB-2485 in the clinical setting.

Effects of different host plants on the growth, development, and fecundity of Phthorimaea absoluta (Lepidoptera: Gelechiidae): an evaluation based on the age-stage two-sex life table.

This study aimed to investigate the growth and development parameters of Phthorimaea absoluta (Meyrick) population at each stage when feeding on 4 host plants: Lycopersicon esculentum, Solanum tuberosum, Solanum melongena, and Nicotiana tabacum. The objective was to predict population dynamics and develop appropriate control strategies. The age-stage sex-life table was used to evaluate survival rate, fecundity, life expectancy, reproductive value, population parameters, and population growth prediction of P. absoluta after feeding on the 4 Solanaceae plants. The results showed significant variations in the fecundity parameters of P. absoluta among the different host plants. The L. esculentum population exhibited the highest average egg-laying period (13.17 ±â€…0.61 days) and average egg production (219.31 ±â€…21.02 eggs), while N. tabacum had the lowest values (4.56 ±â€…0.26 days and 26.08 ±â€…2.53 eggs, respectively). The gross reproduction rate of P. absoluta feeding on L. esculentum was 146.43 ±â€…21.00, which was 1.80, 3.77, and 6.39 times higher compared to S. tuberosum, S. melongena, and N. tabacum, respectively. The average age period and population doubling time of P. absoluta feeding on L. esculentum were lower than those of the other 3 host plants. These results indicated that while P. absoluta can complete a generation on L. esculentum, S. tuberosum, S. melongena, and N. tabacum, L. esculentum is the most suitable host for its growth and development. Therefore, in the occurrence and adjacent areas of P. absoluta, relevant authorities should promptly monitor and control its population in the planting areas of Solanaceae plants to prevent further spread.

Potent bromodomain and extraterminal domain inhibitor JAB-8263 suppresses MYC expression and exerts anti-tumor activity in colorectal cancer models.

BACKGROUND: The overexpression of the MYC gene plays an important role in the occurrence, development and evolution of colorectal cancer (CRC). Bromodomain and extraterminal domain (BET) inhibitors can decrease the function BET by recognizing acetylated lysine residues, thereby downregulating the expression of MYC. AIM: To investigate the inhibitory effect and mechanism of a BET inhibitor on CRC cells. METHODS: The effect of the BET inhibitor JAB-8263 on the proliferation of various CRC cell lines was studied by CellTiter-Glo method and colony formation assay. The effect of JAB-8263 on the cell cycle and apoptosis of CRC cells was studied by propidium iodide staining and Annexin V/propidium iodide flow assay, respectively. The effect of JAB-8263 on the expression of c-MYC, p21 and p16 in CRC cells was detected by western blotting assay. The anti-tumor effect of JAB-8263 on CRC cells in vivo and evaluation of the safety of the compound was predicted by constructing a CRC cell animal tumor model. RESULTS: JAB-8263 dose-dependently suppressed CRC cell proliferation and colony formation in vitro. The MYC signaling pathway was dose-dependently inhibited by JAB-8263 in human CRC cell lines. JAB-8263 dose-dependently induced cell cycle arrest and apoptosis in the MC38 cell line. SW837 xenograft model was treated with JAB-8263 (0.3 mg/kg for 29 d), and the average tumor volume was significantly decreased compared to the vehicle control group (P < 0.001). The MC38 syngeneic murine model was treated with JAB-8263 (0.2 mg/kg for 29 d), and the average tumor volume was significantly decreased compared to the vehicle control group (P = 0.003). CONCLUSION: BET could be a potential effective drug target for suppressing CRC growth, and the BET inhibitor JAB-8263 can effectively suppress c-MYC expression and exert anti-tumor activity in CRC models.

Icotinib inhibits EGFR signaling and alleviates psoriasis-like symptoms in animal models.

To investigate the effects of icotinib hydrochloride and a derivative cream on epidermal growth factor receptor (EGFR) signaling and within animal psoriasis models, respectively. The effect of icotinib on EGFR signaling was examined in HaCaT cells, while its effect on angiogenesis was tested in chick embryo chorioallantoic membranes (CAM). The effectiveness of icotinib in treating psoriasis was tested in three psoriasis models, including diethylstilbestrol-treated mouse vaginal epithelial cells, mouse tail granular cell layer formation, and propranolol-induced psoriasis-like features in guinea pig ear skin. Icotinib treatment blocked EGFR signaling and reduced HaCaT cell viability as well as suppressed CAM angiogenesis. Topical application of icotinib ameliorated psoriasis-like histological characteristics in mouse and guinea pig psoriasis models. Icotinib also significantly inhibited mouse vaginal epithelium mitosis, promoted mouse tail squamous epidermal granular layer formation, and reduced the thickness of the horny layer in propranolol treated auricular dorsal surface of guinea pig. We conclude that icotinib can effectively inhibit psoriasis in animal models. Future clinical studies should be conducted to explore the therapeutic effects of icotinb in humans.