Ciliobrevin A is a hedgehog pathway inhibitor that blocks sonic hedgehog (Shh)-induced hedgehog pathway activation (IC50 = 7 μM). It disrupts primary cilia formation and inhibits the dynein-dependent microtubial gliding and ATPase activities of the cytoplasmic ATPases associated with various cellular activities (AAA+) family. Ciliobrevin A also inhibits mammalian target of rapamycin complex 1 (mTORC1) activity in uninfected and human cytomegalovirus (HCMV)-infected cells, suggesting that mTORC1 activation requires dynein-dependent transport for cellular activation.
Ciliobrevin A is a Hedgehog pathway inhibitor; ciliogenesis inhibitor. The Hedgehog (HH) signaling pathway is targeted for anti-cancer therapeutics. Ciliobrevin A inhibited proliferation of cerebellar granula neuron precursor cells, an important model of HH signaling.
HPI-4 is a Hedgehog pathway inhibitor; ciliogenesis inhibitor. The Hedgehog (HH) signaling pathway is targeted for anti-cancer therapeutics. A key signaling molecule in HH pathway, Smoothened (Smo), has been the target of pharmacological intervention, which has resulted in multiple Smo antagonists including Cyclopamine. However, the oncogenic form of Smo is resistant to Cyclopamine, so the identification of inhibitors of downstream effectors, such as the transcription factors Gli1 and Gli2, is important. Four small molecules were identified to inhibit HH downstream of Smo, HPI-1, HPI-2, HPI-3, and HPI-4. HPI-4 blocked HH pathway activation by SAG, decreased Smo ciliary accumulation, decreased HH activity in a consitutively active HH cell line, and decreased Gli1 and Gli2, processing, and stability. HPI-4 inhibited proliferation of cerebellar granula neuron precursor cells, an important model of HH signaling. Cilia in HPI-4-treated cells were either truncated or absent. The mechanism of action of HPI-4 is hypothesized to be directly through perturbation of ciliogenesis, leading to disruption of Gli1/Gli2 activity, which is distinctly different from that of Cyclopamine.
