Faculty

Anna K. Mapp

Professor of Chemistry

Ph.D., University of California, Berkeley
Postdoctoral Fellow, NIH, California Institute of Technology

Research Focus: Discovery of Artificial Transcriptional Regulators

Phone: 734.615.6862
E-mail: amapp@umich.edu
Fax: 734.615.8553

Researchers in the Mapp laboratory use the tools of synthetic chemistry and cell biology to discover small molecules that target malfunctioning genes with a focus on cancer and metabolic diseases.

Most essential cellular functions are accomplished by dynamic macromolecular assemblies comprised of least one enzymatic component surrounded by non-enzymatic moieties that enforce the timing, location and specificity of the complex function. In the case of transcription, for example, transcriptional activators direct the assembly of the RNA polymerase II holoenzyme at specific gene promoters at particular time points; once the polymerase is engaged, the complex disassembles as transcription initiates (Figure 1). This is accomplished through protein-protein interactions (PPIs) that are dynamic and, in some cases, short-lived.

Mis-regulation of cellular assembly/disassembly events is at the heart of human diseases from cancer to psychiatric disorders, and the PPIs that direct these dynamic processes are ripe for both probe development and therapeutic targeting. Despite their prevalence and functional importance, these PPIs have historically been considered all but impossible for small molecule modulation and are typically classified as ‘undruggable’. The challenge is multi-variable: the binding partners often have significant disorder and are thus difficult to characterize structurally alone or in complex; the surface area of the PPIs is considerably larger than protein-ligand interactions, and the strengths of the interactions are modest.

Nowhere are the promise and the challenge of dynamic PPIs more evident than in the study and targeting of transcriptional activators. The list of activators implicated in human disease continues to grow and yet outside of the nuclear receptor family there are only a handful of small molecules that directly target these proteins, with no drug candidates on the horizon. For just over a decade, our efforts have focused on capturing in vivo the molecular detail of transcriptional activators interacting with the transcriptional machinery, defining the resulting complexes kinetically and thermodynamically and, importantly, transforming these insights into small molecule modulators of these interactions, molecules that can be deployed as mechanistic probes and can be utilized as first-generation, transcription-targeted therapeutics.

 

Figure 1. Small and large molecule transcriptional activators. a) Transcriptional activators associate with particular genes in a signal-response fashion, recruit chromatin re-modeling complexes, and facilitate assembly of the transcriptional machinery (RNA pol II and associated coactivators, core transcription factors). Remarkably a single domain – the transcriptional activation domain (red rectangle) accomplishes most of this through dynamic and moderate affinity binding interactions; b) small molecule mimics of transcriptional activation domains discovered in our laboratory.

Mapp Research Group

 

Awards

CAREER Award, National Science Foundation
Alfred P. Sloan Fellow
Basil O'Connor Starter Scholar Research Award. March of Dimes
New Investigator in the Toxicological Sciences, Burroughs Wellcome Fund
Research Innovation Award, Research Corporation

 

Representative Publications

  1. “Fine-tuning multi-protein complexes using small molecules.” Thompson AD, Dugan A, Gestwicki JE, Mapp AK. ACS Chem Biol. 2012 In press.

  2. “Synergistic enhancement of the potency and selectivity of small molecule transcriptional inhibitors.” Taylor, C.E.; Pan, Q.; Mapp, A.K. ACS Med Chem. Lett. 2012, 3, 30-34.

  3. “Caught in the act: covalent cross-linking captures activator-coactivator interactions in vivo.” Krishnamurthy, M.; Dugan, A.; Nwokoye, A.; Fung, Y.-H.; Lancia, J.K.; Majmudar, C.Y.; Mapp, A.K. ACS Chemical Biology 2011, 6, 1321-6.

  4. “Transforming ligands into transcriptional regulators: building blocks for bi-functional molecules.” Hojfeldt, J.W.; Van Dyke, A.R.; Mapp, A.K. Chem. Soc. Rev. 2011, 40, 4286-94.

  5. “Amphipathic small molecules mimic the binding mode and function of endogenous transcription factors.” S. J. Buhrlage, C. A. Bates, S. P. Rowe, A. R. Minter, B. B. Brennan, C. Y. Majmudar, D. E. Wemmer, H. Al-Hashimi, and A. K. Mapp. ACS Chem. Biol. 2009, 4, 335-44.

  6. “Impact of nonnatural amino acid mutagenesis on the in vivo function and binding modes of a transcriptional activator.” C. Y. Majmudar, L. W. Lee, J. K. Lancia, A. Nwokoye, Q. Wang, L. Wang, and A. K. Mapp. J. Am. Chem. Soc. 2009, 131(40), 14240-14242.

 

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