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Summary

4SC-208 specifically targets two kinases that are crucial for Hedgehog/GLI signaling – a signaling pathway that is critical for tumor development, proliferation and survival.

Inhibition of this pathway has emerged as a highly effective strategy in obstructing the tumorigenic capacity of cancer stem cells responsible for metastasis and the recurrence of tumors.

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Development profile

4SC-208 is a promising drug candidate and 4SC intends to advance the compound into clinical studies in relevant cancer indications, particularly where resistance to therapies targeting the Hedgehog pathways are emerging.

4SC-208 has been evaluated in a number of preclinical in vivo models. Currently, 4SC-208 is in regulatory preclinical testing and is expected to enter Phase I clinical evaluation in 2019.

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Scientific background

Cancer stem cells are found in most cancer indications and are often responsible for tumor recurrence and metastasis. Targeting cancer stem cells is therefore thought of as a key approach to achieve sustained remission.

In cancer stem cells the Hedgehog/GLI signaling pathway is critical. To date, clinical testing of inhibitors that target the Hedgehog pathway are focused upstream of the transcription factor GLI at the level of the cell surface protein SMO. However, Hedgehog signaling in cancer stem cells is mostly activated downstream at GLI level.

4SC-208 is a unique small molecule that directly targets the Hedgehog/GLI signaling pathway downstream of SMO at the level of GLI, giving it the potential to be efficacious in a wide range of hedgehog-dependent cancer indications, but avoiding the major disadvantage of SMO inhibitors, which is acquired resistance. 4SC-208 targets two novel kinases whose role as key regulators of GLI was discovered by 4SC.

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The relevance of downstream Hedgehog signaling was demonstrated in a genetically modified medulloblastoma cell line with constitutive GLI expression and in a number of pancreatic cell lines with TGF-β dependent GLI expression. The SMO antagonist vismodegib has displayed a complete loss of activity in pancreatic tumor cell lines, in contract to 4SC-208, which exhibited good efficacy. These findings underline the superiority of 4SC-208 as inhibitor of Hedgehog/GLI signaling and its effectiveness in cancer stem cells.

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