Breadcrumb

John A. Beutler, Ph.D.

John A. Beutler, Ph.D.

  • Center for Cancer Research
  • National Cancer Institute
Molecular Targets Program

RESEARCH SUMMARY

Dr. Beutler has identified several natural products which have potential for development as cancer drugs, among them, englerins, which are in preclinical development for kidney cancer and Ewing’s sarcoma, schweinfurthins, which are preclinical candidates in glioblastoma and malignant peripheral nerve sheath tumors, and salicylihalamides, of interest in sarcomas. As a Staff Scientist 2, Dr. Beutler oversees the Program's high-throughput screening libraries, information technology, and drug development efforts.

Areas of Expertise

1) natural products chemistry 2) high-throughput screening 3) molecular pharmacology

Publications

Selected Key Publications

Bridgehead modifications of englerin A reduce TRPC4 activity and intravenous toxicity but not cell growth inhibition

Wu Z, Suppo J-S, Tumova S, Strope JD, Bravo F, Moy M, Weinstein ES, Peer CJ, Figg WD, Chain WJ, Echavarren AM, Beech DJ, Beutler JA
ACS Med Chem Lett. 11: 1711-1716, 2020.
Full-Text Article
[ Journal Article ]

Synthesis of a stable and orally bioavailable englerin analogue

Fash DM, Peer CJ, Li Z, Talisman IJ, Hayavi S, Sulzmaier FJ, Ramos JW, Sourbier C, Neckers L, Figg WD, Beutler JA, Chain WJ
Bioorg Med Chem Lett. 26: 2641, 2016. [ Journal Article ]

Synthesis and biological evaluation of new (-)-englerin analogues

López-Suárez L, Riesgo L, Bravo F, Ransom TT, Beutler JA, Echavarren AM
ChemMedChem. 11: 1003, 2016. [ Journal Article ]

Englerin A stimulates PKCθ to inhibit insulin signaling and to simultaneously activate HSF1: pharmacologically induced synthetic lethality

Sourbier C, Scroggins BT, Ratnayake R, Prince TL, Lee S, Lee M, Nagy PL, Lee YH, Trepel JB, Beutler JA, Linehan WM, Neckers L.
Cancer Cell. 23: 228-37, 2013. [ Journal Article ]

Schweinfurthin A selectively inhibits proliferation and Rho signaling in glioma and neurofibromatosis type 1 tumor cells in a NF1-GRD-dependent manner

Turbyville TJ, Gürsel DB, Tuskan RG, Walrath JC, Lipschultz CA, Lockett SJ, Wiemer DF, Beutler JA, Reilly KM.
Mol Cancer Ther. 9: 1234-43, 2010. [ Journal Article ]

Team

Postdoctoral Fellow (Visiting)
Dongdong Wang, Ph.D.
Postdoctoral Fellow (Visiting)
Dayani Sarath Parakumge, Ph.D.
Programmer Analyst IV (Contr.)
Ekaterina I. Goncharova, Ph.D.
IT Manager (Contr.)
Christopher Wolcott

Covers

Structure of neopetrothiazide

Neopetrothiazide, an intriguing pentacyclic thiazide alkaloid from the sponge Neopetrosia sp.

Published Date

Neopetrothiazide (1), a pentacyclic isoquinoline quinone, was isolated from a Neopetrosia sp. sponge. The structure elucidation was facilitated by utilizing long-range heteronuclear single quantum multiple bond correlation (LR-HSQMBC) and heteronuclear multiple bond correlation (HMBC) nuclear magnetic resonance (NMR) pulse sequences optimized to detect four- and five-bond (1)H-(13)C heteronuclear correlations. These NMR experiments can help assign proton-deficient structural motifs like neopetrothiazide (1), which has 14 contiguous nonprotonated centers (C, N, and S). Neopetrothiazide (1), with an unprecedented thiazide-fused structural scaffold, is the first natural product containing a thiazide moiety.

Citation

Wang D, Jiang W, Kim CK, Bokesch HR, Woldemichael GM, Gryder BE, Shern JF, Khan J, O'Keefe BR, Beutler JA, Gustafson KR. Neopetrothiazide, an intriguing pentacyclic thiazide alkaloid from the sponge Neopetrosia sp. Org Lett 23: 3278-3281, 2021.
 

Synthesis and biological assessment of 3,7-dihydroxytropolones

Synthesis and biological assessment of 3,7-dihydroxytropolones

Published Date

3,7-Dihydroxytropolones (3,7-dHTs) are highly oxygenated troponoids that have been identified as lead compounds for several human diseases. To date, structure-function studies on these molecules have been limited due to a scarcity of synthetic methods for their preparation. New synthetic strategies towards structurally novel 3,7-dHTs would be valuable in further studying their therapeutic potential. Here we describe the successful adaptation of a [5 + 2] oxidopyrilium cycloaddition/ring-opening for 3,7-dHT synthesis, which we apply in the synthesis of a plausible biosynthetic intermediate to the natural products puberulic and puberulonic acid. We have also tested these new compounds in several biological assays related to human immunodeficiency virus (HIV), hepatitis B virus (HBV) and herpes simplex virus (HSV) in order to gain insight into structure-functional analysis related to antiviral troponoid development.

Citation

Hirsch DR, Schiavone DV, Berkowitz AJ, Morrison LA, Masaoka T, Wilson JA, Lomonosova E, Zhao H, Patel BS, Datla SH, Hoft SG, Majidi SJ, Pal RK, Gallicchio E, Tang L, Tavis JE, Le Grice SFJ, Beutler JA, Murelli RP. Synthesis and biological assessment of 3,7-dihydroxytropolones. Organic & biomolecular chemistry 2018; 16: 62-69.

Alumni

Marshall Darby
Marshall Darby
2017-2018
Werner Kersten Intern
Esra Eroglu Ozkan
Esra Eroglu Ozkan
2017-2018
Special Volunteer
Sarah Long photo
Sarah Long
2015-2018
IRTA Fellow
Memnune Erucar photo
Fatma Memnune Erucar
2019-2020
Fulbright Fellow
Laila Espindola
Laila Espindola Darvenne
2014-2015
Special Volunteer
Marcos da Cunha
Marcos da Cunha
2013-2014
Special Volunteer
Namki Cho
Namki Cho
2014-2016
Visiting Fellow
Sett Naing
Sett Naing
2012-2013; 2014, 2017
Werner Kirsten Intern and Summer Student
Krishna Devkota photo
Krishna Devkota
2010-2013
Visiting Fellow
Ranjala Ratnayake photo
Ranjala Ratnayake
2007-2009
Visiting Fellow

Lab Life

Shaking hands with Steve Chu at AAAS Fellows reception in Seattle, just pre-COVID.

Shaking hands with Steve Chu at AAAS Fellows reception in Seattle, just pre-COVID.

Carving pumpkins

Group get together to carve pumpkins and eat good food.