Optimizing the linker of venetoclax-artemisinin conjugates to improve water solubility and antileukemia effects

Venetoclax based combination therapy is utilized as the first-line treatment for elderly acute myeloid leukemia (AML) patients with short remission time due to resistance and relapse. Previously, we reported that artesunate enhanced venetoclax-induced apoptosis by promoting NOXA-mediated degradation of Mcl-1. By employing a chemical conjugation approach, we linked dihydroartemisinin (DHA) to venetoclax using a two-carbon methylene spacer, yielding the conjugate A1. A1 maintains Bcl-2 inhibitory activity and overcomes Mcl-1/Bcl-xL-mediated resistance. However, due to its large molecular size, A1 has limited bioavailability and solubility. To address these limitations, we incorporated various polyethylene glycol (PEG) units between venetoclax and DHA, generating conjugates A18-A20. These derivatives exhibited approximately two-fold greater solubility than A1, and more potent activity to inhibit colony formation of U937 cells in soft agar assays. Moreover, A19 and A20 significantly suppressed tumor growth in vivo. The tumor growth inhibition rates for A19 and A20 (75.6% and 65.8%, respectively) were significantly higher than that of venetoclax alone (33.9%). We further modified the PEG backbone of A20 by incorporating nitrogen-containing polar groups, resulting in compounds A21-A23. These modifications led to further increased aqueous solubility and colony-forming inhibitory activity. These novel conjugates represent promising next-generation venetoclax derivatives capable of overcoming resistance.