Skip to main content
An official website of the United States government
Email

The Molecular Pharmacology Branch (MPB)

Kaplan-Meier curve

MPB's mission is to improve the treatment of recalcitrant, rare and neglected cancers through the discovery of potential therapeutic targets, the screening of new agents, the identification of genomic vulnerabilities, and the identification of potential therapeutic combinations that collectively use state-of-the-art drug discovery, molecular characterization and mechanism-of-action techniques combined with interactive collaborations within the cancer research community and other NCI laboratories. The MPB operates five laboratories at the Frederick National Laboratories for Cancer Research: The NCI60 cell line screen; The Target Validation and Screening Laboratory which specializes in drug combination studies in patient-derived complex spheroids; The Organoids Laboratory; The Translational Support Laboratory and The Tubulin Biology Laboratory. MPB is currently focused on 3D patient-derived models with an emphasis on rare and recalcitrant cancers from the PDMR collection.

NCI60 HTS384 Screening Laboratory

The NCI60 HTS384 Screening Laboratory is responsible for running the NCI60 cell line screen as a resource for the research community. The screen is run on a regular schedule to evaluate new agents submitted by investigators.

  1. Kunkel MW, Coussens NP, Morris J, Taylor RC, Dexheimer TS, Jones EM, Doroshow JH, Teicher BA. HTS384 NCI60: The Next Phase of the NCI60 Screen. Cancer Res. 2024; 84: 2403-16.
  2. Joel Morris, Mark W Kunkel, Stephen L White, Donn G Wishka, Omar D Lopez, Lori Bowles, Penny Sellers Brady, Patricia Ramsey, Julie Grams, Tiffany Rohrer, Karen Martin, Thomas S Dexheimer, Nathan P Coussens, David Evans, Prabhakar Risbood, Dmitriy Sonkin, John D Williams, Eric C Polley, Jerry M Collins, James H Doroshow, Beverly A Teicher Targeted Investigational Oncology Agents in the NCI-60: A Phenotypic Systems-based Resource Mol Cancer Ther. 2023 Aug 7;22(11):1270-1279.
  3. Monks A, Zhao Y, Hose C, Hamed H, Krushkal J, Fang J, Sonkin D, Palmisano A, Polley EC, Fogli LK, Konaté MM, Miller SB, Simpson MA, Voth AR, Li MC, Harris E, Wu X, Connelly JW, Rapisarda A, Teicher BA, Simon R, Doroshow JH. The NCI Transcriptional Pharmacodynamics Workbench: A Tool to Examine Dynamic Expression Profiling of Therapeutic Response in the NCI-60 Cell Line Panel. Cancer Res 2018; 78: 6807-17.

Target Validation and Screening Laboratory

The Target Validation and Screening Laboratory has the infrastructure and expertise to perform a wide range of biochemical and cell-based assays including high-throughput screens of single agents and combinations of agents. Experimental systems include patient-derived tumor models, established in vitro cell cultures, and monolayer and 3D multi-cell type and tumor spheroid models. Characterizations are run using a fully automated 384-well screening system with endpoint or multiplex assays by measurements of luminescence, fluorescence, absorbance, and bright-field and high content imaging. The screening libraries are composed of compounds with largely defined mechanism(s) of action which are in clinical use or under active clinical investigation, providing a facile pathway for clinical translation of active compounds from the screen. Additionally, the results of these screens might define potential new targets for drug discovery against rare, recalcitrant or neglected cancers.

  1. Sonkin D, Thomas A, Teicher BA. Cancer treatments: Past, present, and future. Cancer Genet. 2024; 286-287:18-24.
  2. Dexheimer TS, Coussens NP, Silvers T, Jones EM, Chen L, Fang J, Morris J, Moscow JA, Doroshow JH, Teicher BA. Combination screen in multi-cell type tumor spheroids reveals interaction between aryl hydrocarbon receptor antagonists and E1 ubiquitin-activating enzyme inhibitor. SLAS Discov 2024; 29: 100186.
  3. Dexheimer TS, Coussens NP, Silvers T, Wright J, Morris J, Doroshow JH, Teicher BA. Multicellular Complex Tumor Spheroid Response to DNA Repair Inhibitors in Combination with DNA-damaging Drugs. Cancer Res Commun. 2023; 3:1648-61.
  4. Kaur G, Evans DM, Teicher BA, Coussens NP. Complex tumor spheroids, a tissue-mimicking tumor model, for drug discovery and precision medicine. SLAS DISCOVERY: Advancing the Science of Drug Discovery 2021; 26: 1298-1314.
  5. Krushkal J, Silvers T, Reinhold WC, Sonkin D, Vural S, Connelly J, Varma S, Meltzer PS, Kunkel M, Rapisarda A, Evan, D. Epigenome-wide DNA methylation analysis of small cell lung cancer cell lines suggests potential chemotherapy targets. Clinical Epigen 2020; 12: 1-28.
  6. Evans DM, Fang, J, Silvers T, Delosh R, Laudeman J, Ogle C, Reinhart R, Selby M, Bowles L, Connelly J, Harris E. Exposure time versus cytotoxicity for anticancer agents. Cancer Chemotherap Pharmacol 2017; 84: 359-71.
  7. Selby M, Delosh R, Laudeman J, Ogle C, Reinhart R, Silvers T, Lawrence S, Kinders R, Parchment R, Teicher BA, Evans DM. 3D models of the NCI60 cell lines for screening oncology compounds. SLAS DISCOVERY: Advancing Life Sciences R&D 2017; 22: 473-83.
  8. Teicher BA, Silvers T, Selby M, Delosh R, Laudeman J, Ogle C, Reinhart R, Parchment R, Krushkal J, Sonkin D, Rubinstein L. Small cell lung carcinoma cell line screen of etoposide/carboplatin plus a third agent. Cancer Medicine 2017; 6: 1952-64.
  9. Polley E, Kunkel M, Evans D, Silvers T, Delosh R, Laudeman J, Ogle C, Reinhart R, Selby M, Connelly J, Harris E, Fer N, Sonkin D, Kaur G, Monks A, Malik S, Morris J, Teicher BA. Small cell lung cancer screen of oncology drugs, investigational agents, and gene and microRNA expression. J Nat Cancer Inst 2016; 108: djw122.
  10. Teicher BA, Polley E, Kunkel M, Evans D, Silvers T, Delosh R, Laudeman J, Ogle C, Reinhart R, Selby M, Connelly J. Sarcoma cell line screen of oncology drugs and investigational agents identifies patterns associated with gene and microRNA expression. Molec Cancer Therap 2015; 14: 2452-62.

Organoid Screening Laboratory

The Organoid Screening Laboratory works with organoid cultures from the patient-derived models' program or from normal or malignant tissues obtained from surgical resections and patient biopsies or from mice to evaluate anticancer single agents or combinations. The organoid cultures are characterized for morphological properties and growth characteristics along with the development of appropriate culturing conditions, handling methodologies, and assays for automated drug screening. Screens include FDA approved anticancer agents and investigational agents as single agent or combinations with endpoint or multiplex assays by measurements of luminescence, fluorescence, absorbance, and bright-field and high content imaging.

  1. El Touny LH, Hose C, Connelly J, Harris E, Monks A, Dull AB, Wilsker DF, Hollingshead MG, Gottholm-Ahalt M, Alcoser SY, Mullendore ME, Parchment RE, Doroshow JH, Teicher BA, Rapisarda A. ATR inhibition reverses the resistance of homologous recombination deficient MGMTlow/MMRproficient cancer cells to temozolomide. Oncotarget 2021; 12: 2114-30.

Tubulin Biochemistry and Pharmacology Laboratory

The Tubulin Biochemistry and Pharmacology Laboratory is interested in all aspects of tubulin biochemistry and pharmacology, particularly the discovery and analysis of novel molecular entities and how they interact with tubulin. This laboratory joined the Developmental Therapeutics Program in 1996 and assists extramural laboratories by leveraging expertise in evaluating entities that interact with all drug binding sites on tubulin. The laboratory is engaged in multiple extramural collaborations with research groups all over the world.

  1. Ren W, Deng Y, Ward JD, Vairin R, Bai R, Wanniarachchi H I, Hamal KB, Tankoano PE, Tamminga CS, Bueno LMA, Hamel E, Mason RP, Trawick ML, Pinney KG. Synthesis and biological evaluation of structurally diverse 6-aryl-3-aroyl-indole analogues as inhibitors of tubulin polymerization. Eur J Med Chem 2024; 263: 115794.
  2. Milunovic MNM, Ohui K, Besleaga I, Petrasheuskaya TV, Dömötör O, Enyedy ÉA, Darvasiova D, Rapta P, Barbieriková Z, Vegh D, Tóth S, Tóth J, Kucsma N, Szakács G, Popovic-Bijelic A, Zafar A, Reynisson J, Shutalev AD, Bai R, Hamel E, Arion V B. Copper(II) complexes with isomeric morpholine-substituted 2-formylpyridine thiosemicarbazone hybrids as potential anticancer drugs inhibiting both ribonucleotide reductase and tubulin polymerization: the morpholine position matters. J Med Chem 2024; 67: 9069-90.
  3. Arion V, Besleaga I, Raptova R, Stoica AC, Milunovic M, Zalibera M, Bai R, Igaz N, Reynisson J, Kiricsi M, Enyedy E, Rapta P, Hamel E. Are the metal identity and stoichiometry of metal complexes important for colchicine site binding and inhibition of tubulin polymerization? Dalton Trans 2024; 53: 12349-69.
  4. Mariotto E, Canton M, Marchioro C, Brancale A, Hamel E, Varani K, Vincenzi F, De Ventura T, Padroni C, Viola G, Romagnoli R. Benzofuran-based hydroxamic acids as antimicrotubule agents. Int J Mol Sci 2024; 25: 7519 (35 pps).
  5. Kong Y, Edler MC, Hamel E, Britton-Jenkins AR, Gillan O, Mooberry SL, Mu D, Brown ML. Synthesis and structure-activity relationship of boronic acid bioisosteres of combretastatin A-4 as anticancer agents. Bioorg Med Chem 2024; 116: 117999 (10 pps).
  6. Ford JW, VanNatta JM, Mondal D, Lin CM, Den Y, Bai R, Hamel E, Trawick ML, Pinney KG. Drug-linker constructs bearing unique dual-mechanism tubulin binding payloads tethered through cleavable and non-cleavable linkers. Tetrahedron 2025; 171:134350 (17 pps).
  7. Vairin R, Tamminga C, Shi Z, Borchardt C, Jambulapati J, Bai R, Wanniarachchi H, Bueno L, Hamel E, Mason RP, Trawick ML, Pinney KG. Design, Synthesis and biological evaluation of 2-phenyl indole analogues of OXi8006 as colchicine site inhibitors of tubulin polymerization and vascular disrupting agents. Bioorg Med Chem 2025; 118: 117981 (17 pps).
  8. Spanò V, Barreca M, Rocca R, Bortolozzi R, Bai R, Carbone A, Raimondi MV, Piccionello AP, Montalbano A, Alcaro S, Hamel E, Viola G, Barraja P. Insight on [1,3]thiazolo[4,5-e]isoindoles as tubulin polymerization inhibitors. Eur J Med Chem 2021; 212: 113122.
  9. Choudhary S, Doshi A, Luckett-Chastain L, Ihnat M, Hamel E, Mooberry SL, Gangjee A. Potential of substituted quinazolines to interact with multiple targets in the treatment of cancer. Bioorg Med Chem 2021; 35: 116061.
  10. Peerzada MN, Hamel E, Bai R, Supuran CT, Azam A. Deciphering the key heterocyclic scaffolds in targeting microtubules, kinases and carbonic anhydrases for cancer drug development. Pharmacol Ther 2021; 225: 107860.

Mechanism of Action Laboratory

The Mechanism of Action Laboratory is the newest component of the Molecular Pharmacology Branch. It is analyzing single agent and combination screening data against a range of cancer types in combination with cheminformatics with the goal of identifying synergistic drug combinations for further possible study as candidates for therapeutic development.

Selected References

  1. Ren W, Deng Y, Ward JD, Vairin R, Bai R, Wanniarachchi H I, Hamal KB, Tankoano PE, Tamminga CS, Bueno LMA, Hamel E, Mason RP, Trawick ML, Pinney KG. Synthesis and biological evaluation of structurally diverse 6-aryl-3-aroyl-indole analogues as inhibitors of tubulin polymerization. Eur J Med Chem 2024; 263: 115794. 

    [PubMed Abstract]

  2. Milunovic MNM, Ohui K, Besleaga I, Petrasheuskaya TV, Dömötör O, Enyedy ÉA, Darvasiova D, Rapta P, Barbieriková Z, Vegh D, Tóth S, Tóth J, Kucsma N, Szakács G, Popovic-Bijelic A, Zafar A, Reynisson J, Shutalev AD, Bai R, Hamel E, Arion V B. Copper(II) complexes with isomeric morpholine-substituted 2-formylpyridine thiosemicarbazone hybrids as potential anticancer drugs inhibiting both ribonucleotide reductase and tubulin polymerization: the morpholine position matters. J Med Chem 2024; 67: 9069-90.

    [PubMed Abstract]

  3. Arion V, Besleaga I, Raptova R, Stoica AC, Milunovic M, Zalibera M, Bai R, Igaz N, Reynisson J, Kiricsi M, Enyedy E, Rapta P, Hamel E. Are the metal identity and stoichiometry of metal complexes important for colchicine site binding and inhibition of tubulin polymerization? Dalton Trans 2024; 53: 12349-69.

    [PubMed Abstract]

  4. Mariotto E, Canton M, Marchioro C, Brancale A, Hamel E, Varani K, Vincenzi F, De Ventura T, Padroni C, Viola G, Romagnoli R. Synthesis and Biological Evaluation of Novel 2-Aroyl Benzofuran-based hydroxamic acids as antimicrotubule agents. Int J Mol Sci 2024; 25: 7519 (35 pps).

    [PubMed Abstract]

  5. Kong Y, Edler MC, Hamel E, Britton-Jenkins AR, Gillan O, Mooberry SL, Mu D, Brown ML. Synthesis and structure-activity relationship of boronic acid bioisosteres of combretastatin A-4 as anticancer agents. Bioorg Med Chem 2024; 116: 117999 (10 pps).

    [PubMed Abstract]

  6. Ford JW, VanNatta JM, Mondal D, Lin CM, Den Y, Bai R, Hamel E, Trawick ML, Pinney KG. Drug-linker constructs bearing unique dual-mechanism tubulin binding payloads tethered through cleavable and non-cleavable linkers. Tetrahedron 2025; 171:134350 (17 pps).

    [PubMed Abstract]

  7. Vairin R, Tamminga C, Shi Z, Borchardt C, Jambulapati J, Bai R, Wanniarachchi H, Bueno L, Hamel E, Mason RP, Trawick ML, Pinney KG. Design, Synthesis and biological evaluation of 2-phenyl indole analogues of OXi8006 as colchicine site inhibitors of tubulin polymerization and vascular disrupting agents. Bioorg Med Chem 2025; 118: 117981 (17 pps).

    [PubMed Abstract]

  8. Spanò V, Barreca M, Rocca R, Bortolozzi R, Bai R, Carbone A, Raimondi MV, Piccionello AP, Montalbano A, Alcaro S, Hamel E, Viola G, Barraja P. Insight on [1,3]thiazolo[4,5-e]isoindoles as tubulin polymerization inhibitors. Eur J Med Chem 2021; 212: 113122.

    [PubMed Abstract]

  9. Choudhary S, Doshi A, Luckett-Chastain L, Ihnat M, Hamel E, Mooberry SL, Gangjee A. Potential of substituted quinazolines to interact with multiple targets in the treatment of cancer. Bioorg Med Chem 2021; 35: 116061.

    [PubMed Abstract]

  10. Peerzada MN, Hamel E, Bai R, Supuran CT, Azam A. Deciphering the key heterocyclic scaffolds in targeting microtubules, kinases and carbonic anhydrases for cancer drug development. Pharmacol Ther 2021; 225: 107860.

    [PubMed Abstract]
  • Posted:

If you would like to reproduce some or all of this content, see Reuse of NCI Information for guidance about copyright and permissions. In the case of permitted digital reproduction, please credit the National Cancer Institute as the source and link to the original NCI product using the original product's title; e.g., “The Molecular Pharmacology Branch (MPB) was originally published by the National Cancer Institute.”

Email