4SC-208 is a small molecule specifically targeting two kinases crucial for Hedgehog/GLI signaling. The Hedgehog/GLI signaling pathway 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 recurrence of tumors.

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Development profile

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

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

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Scientific background

Cancer stem cells are found in most cancer indications and are responsible for tumor recurrence and metastasis. Targeting cancer stem cells is therefore thought to be one of the key methods to achieve sustained remission.

In cancer stem cells the Hedgehog/GLI signaling pathway is critical. To date in the industry, clinically tested Hedgehog inhibitors target the Hedgehog pathway upstream of the transcription factor GLI at the level of the SMO protein. However, Hedgehog signaling in CSCs is mostly activated downstream at GLI level.

4SC-208 is a unique small molecule that is directly targeting the Hedgehog/GLI signaling pathway downstream of the regulator SMO at the level of GLI, giving it a wide range of applicability in hedgehog-dependent cancer indications while at the same time avoiding the major disadvantage of SMO inhibitors: 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 for downstream HH signaling was demonstrated both in a genetically modified medulloblastoma cell line with constitutive GLI expression and in pancreatic cell lines with TGF-β dependent GLI expression. The SMO antagonist vismodegib has displayed complete loss of activity in pancreatic tumor cell lines, whereas 4SC-208 has exhibited good efficacy. These findings underline the superiority of 4SC-208 as inhibitor of Hedgehog/GLI signaling and confirm the effectiveness in cancer stem cells, while SMO inhibitors remain ineffective.

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