DDX5 degrader FL118

An orally bioavailable small molecule derivative of camptothecin, a component found in the bark and stem of a tree native to China, and a degrader of the oncoprotein DEAD box polypeptide 5 (DDX5; RNA helicase p68), with potential antineoplastic activity. Upon oral administration, DDX5 degrader FL118 targets, binds to, dephosphorylates, and degrades DDX5 via the proteasome degradation pathway. This inhibits the expression of DDX5. As DDX5 is a key regulator for controlling the expression of multiple oncogenic proteins, including several members of the inhibitor of apoptosis (IAP) family, such as survivin, XIAP, and cIAP2, and the Bcl-2 family, such as Mcl-1, and other proteins such as c-Myc and mutant KRAS, FL118 is able to inhibit the expression of these various oncoproteins that play key roles in tumor cell proliferation and survival. This increases apoptosis and decreases growth in DDX5-overexpressing tumor cells. In addition, FL118 may affect and suppress cancer stem cells (CSCs). DDX5, overexpressed in many types of cancer while not expressed in normal tissue, plays a crucial role in promoting cancer-associated gene transcription and expression, and in tumor development, progression, metastasis and treatment resistance.