Design and synthesis of emodin derivatives as novel inhibitors of ATP-citrate lyase

Aberrant cellular metabolism drives cancer proliferation and metastasis. ATP citrate lyase (ACL) plays a critical role in generating cytosolic acetyl CoA, a key building block for de novo fatty acid and cholesterol biosynthesis. ACL is overexpressed in cancer cells, and siRNA knockdown of ACL limits cancer cell proliferation and reduces cancer stemness. We characterized a new class of ACL inhibitors bearing the key structural feature of the natural product emodin. Structure-activity relationship (SAR) study led to the identification of 1d as a potent lead that demonstrated dose-dependent inhibition of proliferation and cancer stemness of the A549 lung cancer cell line. Computational modeling indicates this class of inhibitors occupies an allosteric binding site and blocks the entrance of the substrate citrate to its binding site. [Display omitted] •Emodin anthraquinones inhibited the enzymatic activity ATP-citrate lyase (ACL), a key player in cancer cell metabolism.•Lead compound 1d inhibited A549 lung cancer cell proliferation and reduced the stemness of A549 cells.•Docking suggested that anthraquinone inhibitors occupied an allosteric site adjacent to the citrate-binding domain of ACL.