Discovery of 5‑Phenylthiazol-2-amine Derivatives as Novel PI4KIIIβ Inhibitors with Efficacious Antitumor Activity by Inhibiting the PI3K/AKT Axis

To develop novel PI4KIIIβ inhibitors and explore their antitumor activity, a series of 5-phenylthiazol-2-amine derivatives were synthesized by structural modifications of PIK93. Biological assay results indicated that compounds 16 and 43 exhibited superior PI4KIIIβ selective inhibitory and antiproliferative activity than PIK93. Mechanistic studies revealed that the two compounds inhibit the PI3K/AKT pathway more effectively, thereby inducing cancer cell apoptosis, cycle arrest in the G2/M phase and autophagy. Importantly, in vivo toxicity and pharmacodynamics studies showed that compounds 16 and 43 exhibited superior safety to that of commercially available PI3K/AKT axis inhibitor alpelisib, and obviously antitumor activity in small cell lung cancer H446 xenograft models. Overall, this work highlights the therapeutic potential and safety of PI4KIIIβ inhibitors 16 and 43 in the treatment of tumors, and provides candidates and viable drug development strategies for the treatment of small cell lung cancer and the development of novel PI3K/AKT axis inhibitors.