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 <b>16</b> and <b>43</b> 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 <b>16</b> and <b>43</b> 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 <b>16</b> and <b>43</b> 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.