Discovery of the Hedgehog Pathway Inhibitor Pipinib that Targets PI4KIIIß

Abstract

The Hedgehog (Hh) signaling pathway is crucial for vertebrate embryonic development, tissue homeostasis and regeneration. Hh signaling is upregulated in basal cell carcinoma and medulloblastoma and Hh pathway inhibitors targeting the Smoothened (SMO) protein are in clinical use. However, the signaling cascade is incompletely understood and novel druggable proteins in the pathway are in high demand. We describe the discovery of the Hh‐pathway modulator Pipinib by means of cell‐based screening. Target identification and validation revealed that Pipinib selectively inhibits phosphatidylinositol 4‐kinase IIIβ (PI4KB) and suppresses GLI‐mediated transcription and Hh target gene expression by impairing SMO translocation to the cilium. Therefore, inhibition of PI4KB and, consequently, reduction in phosphatidyl‐4‐phosphate levels may be considered an alternative approach to inhibit SMO function and thus, Hedgehog signaling.

RhIII‐Catalyzed C−H Activation of Aryl Hydroxamates for the Synthesis of Isoindolinones

“…Hh signaling is essential during embryonic development and is of importance for stem cell homeostasis and tissue regeneration . Abnormal regulation of Hh signaling is involved in severe birth defects and various types of cancer, including basal cell carcinoma and medulloblastoma . Consequently, the identification of Hh signaling inhibitors is of high interest.…”

“…Consequently, the identification of Hh signaling inhibitors is of high interest. To investigate the effect of selected isoindolinones and isoindolobenzazepines on Hh signaling, a Hh‐dependent osteoblast differentiation assay using C3H10T1/2 cells was employed for primary screening . The Hh pathway was activated using the Smoothened agonist purmorphamine.…”

circSLC6A6 Sponges miR-497-5p to Promote Endometrial Cancer Progression via the PI4KB/Hedgehog Axis

“…In this study, PI4KB was selected as the target gene of miR-497-5p for further exploration. Hedgehog signaling is upregulated in basal cell carcinoma and medulloblastoma, and PI4KB may be a relevant target protein for pharmacological inhibition of Hh signaling [ 17 ]. The binding sites of miR-497-5p and PI4KB are shown in Figure 4(a) .…”

“…Hedgehog (Hh) signaling, firstly discovered in Drosophila by genetic analysis, is highly conserved in evolution and function and essential in the development of normal embryos [ 15 , 16 ]. And the abnormal activation of Hh signaling promotes the cancer progression [ 17 – 19 ]. Phosphatidylinositol 4-kinase III β (PIK4B), regulating cellular physiological functions that contain cell morphology, metabolic regulation, and signal transduction, can produce PI4P that participates in Hh signaling in the dictyosome [ 17 ].…”

“…And the abnormal activation of Hh signaling promotes the cancer progression [ 17 – 19 ]. Phosphatidylinositol 4-kinase III β (PIK4B), regulating cellular physiological functions that contain cell morphology, metabolic regulation, and signal transduction, can produce PI4P that participates in Hh signaling in the dictyosome [ 17 ]. And the disruption of signaling transduction from PTC to SMO that controls PI4P is considered the most common feature in the tumor [ 20 ].…”