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Chronic lymphocytic leukemia

Creating novel translation inhibitors to target pro-survival proteins in chronic lymphocytic leukemia

Leukemia (2019) | Download Citation

Abstract

The viability of chronic lymphocytic leukemia (CLL) is critically dependent upon staving off death by apoptosis, a hallmark of CLL pathophysiology. 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. 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. However, avid binding to human plasma proteins limited DMDAPatA potency, precluding further development. To address this, we synthesized a new series of PatA analogs and identified three new leads with potent inhibition of translation. They exhibited less plasma protein binding and increased cytotoxic potency toward CLL cells than DMDAPatA, with greater selectivity towards CLL cells over normal lymphocytes. Computer modeling analysis correlated 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.

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Acknowledgements

This study was supported in part by research funding to DR and WP from a High-Impact/High-Risk Research Award from The Cancer Prevention and Research Institute of Texas, RP130660, by the CLL Global Research Foundation and the M.D. Anderson Cancer Center Moon Shots Program and cancer center support grant P30CA16622.

Author information

Author notes

    • Qun Qin

    Present address: Xiangya Hospital, Central South University, Changsha, Hunan, China

  1. The authors contributed equally: Rong Chen, Mingzhao Zhu

Affiliations

  1. Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    • Rong Chen
    • , Rajan R. Chaudhari
    • , Yuling Chen
    • , Wesley Skillern
    • , Qun Qin
    • , Shuxing Zhang
    •  & William Plunkett
  2. Department of Chemistry and Biochemistry & CPRIT Synthesis & Drug-Lead Discovery Laboratory, Baylor University, Waco, TX, USA

    • Mingzhao Zhu
    • , Kenneth G. Hull
    •  & Daniel Romo
  3. Department of Chemistry & Natural Products LINCHPIN Laboratory, Texas A&M University, College Station, TX, USA

    • Mingzhao Zhu
    • , Omar Robles
    • , Kenneth G. Hull
    •  & Daniel Romo
  4. Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    • William G. Wierda
    •  & William Plunkett

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Conflict of interest

The authors declare that they have no conflict of interest.

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Correspondence to Daniel Romo or William Plunkett.

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DOI

https://doi.org/10.1038/s41375-018-0364-x