Small molecule targeting of transcription-replication conflict for selective chemotherapy

Abstract

Copyright and License

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Acknowledgement

The authors thank Dr. Steven L. Vonderfecht for his assistance in carrying out the toxicology study. This work was supported in part by research awards to LHM from the Department of Defense (W81XWH-11-1-0786), National Institutes of Health/National Cancer Institute (R01 CA121289), St Baldrick's Foundation (www.stbaldricks.org), the Alex's Lemonade Stand Foundation for Childhood Cancer (Rich Award), Tobacco-Related Disease Research Program (TRDRP-T31IP626), Melanoma Research Foundation (MRF-717178), and the ANNA Fund (www.annafund.com), to Y.L. from National Institutes of Health/National Cancer Institute (R01 CA225843), to K.S.A. from the Raikes Foundation, to R.J.H. and J.J.P.P. from CDMRP of the Department of Defense (W81XWH-19-1-0326 under BC181474 and BC181474P1, respectively). In addition, research reported in this publication was supported by the Analytical Pharmacology Core supported by the National Cancer Institute of the National Institutes of Health under grant number P30CA033572. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Congressionally Directed Medical Research Programs. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Contributions

L.H.M., R.J.H., Y.L., V.C., D.V.H., K.S.A., J.J.P.P., and L.G. conceptualized the idea and supervised the project; L.G., M.L., R.L., J.J., and C.M.L. designed and performed most experiments; T.W.S. designed and supervised the pharmacokinetics studies; D.H and P.H. were responsible for the design and synthesis of the analog compounds; M.G., L.F., and C.H. performed the in vivo combination therapy study; J.J. primarily performed the crystallography studies with support from N.K.; H.L. performed the computer modeling analysis; B.L. performed the proteomic study; H.L. analyzed the proteomic data; L.G. and J.J.P.P. wrote the manuscript.

Data Availability

• Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.
• This paper does not report any original code.
• Protein-ligand crystallization data have been deposited at Protein Data Bank archive and are publicly available as of the date of publication. Accession numbers are listed in the key resources table.

Conflict of Interest

The authors declare the following competing financial interest(s): City of Hope's Office of Technology Licensing has been awarded a patent on AOH1996 and its analogs. L.H. Malkas, R.J. Hickey, D. Horne, and L. Gu are listed as inventors.