Abstract 1854: Novel pateamine analogs to target the translation initiation factor eIF4A in chronic lymphocytic leukemia

Abstract

Abstract The viability of chronic lymphocytic leukemia (CLL) is critically dependent upon staving off death by apoptosis, a hallmark of CLL pathophysiology. The overexpression of the Bcl-2 family proteins likely play a major role in the apoptosis blockade in CLL, and has been an effective target of CLL therapy. The recognition that Mcl-1, a major component of the anti-apoptotic response, is intrinsically short-lived and must be continually resynthesized suggested a novel therapeutic approach. Pateamine A (PatA), a macrolide marine natural product, inhibits cap-dependent translation by binding to the initiation factor eIF4A. We have previously reported the first total synthesis of PatA. Mechanistic studies suggested that binding of eIF4A to PatA caused the stalling of initiation complexes on mRNA, halting the translation initiation process. In this study, we demonstrated that a synthetic derivative of PatA, des-methyl des-amino PatA (DMDAPatA), blocked mRNA translation, reduced Mcl-1 protein and initiated apoptosis in CLL cells. This action was synergistic with the Bcl-2 antagonist ABT-199, by a mechanism to inhibit the two parallel arms of apoptosis control in CLL. However, avid binding to human plasma proteins limited DMDAPatA potency, precluding further development. To address this, we synthesized a new series of 27 PatA analogs with modifications on various regions of PatA, and screened their toxicity against the primary CLL cells. Any modifications on the side chain, or the rigid binding domain of the PatA macrolide ring led to complete loss of activity. Rather, introduction of an amino group at either the C2 or C3 positions of the flexible region of the macrocycle retained the activity and reduced plasma protein binding, likely through a lowered lipophilicity. We identified three new leads with potent inhibition of proteins synthesis and strong CLL cytotoxicity. They also exhibited greater selectivity towards CLL cells over normal lymphocytes comparing to the parental compound PatA. To gain structural insights into the interaction of the PatA analogs with eIF4A, a homology model of the human eIF4A1 was generated using the closed conformation of the eIF4A3 structure (PDB ID: 2HYI) as a template. The predicted PatA binding site is located at the interface of the N-terminal domain and the C-terminal domain, in between the RNA and ATP binding sites. In silico docking analysis of the PatA analogs to eIF4A correlated with their structure-activity relationships and suggested that these compounds may act by stabilizing the closed conformation of eIF4A. Thus, these novel PatA analogs hold promise for application to cancers within the appropriate biological context, such as CLL. Citation Format: Rong Chen, Mingzhao Zhu, Rajan R. Chaudhari, Omar Robles, Yuling Chen, Wesley Skillern, Qun Qin, William Wierda, Shuxing Zhang, Kenneth G. Hull, Daniel Romo, William Plunkett. Novel pateamine analogs to target the translation initiation factor eIF4A in chronic lymphocytic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1854.