The Targeted Therapeutic Drug Discovery & Development Program (TTP) provides researchers with access to cutting-edge technologies and expertise to enable the translation of their research into new treatments for cancers. The goal of TTP is focused on assisting cancer scientists and clinicians by utilizing a truly integratedapproach of targeted molecular drug discovery, uniting every key discipline to achieve their goals in a single platform. We believe that having such an integrated platform will increase the number of new compounds in Texas reaching the stage of pre-clinical testing that possess the potency, selectivity and pharmacokinetic parameters needed to engage and inhibit oncogenic targets in tumors.
For more information on how to collaborate with the program go to TTP
Current appointment
Johnson & Johnson Centennial Professor, The University of Texas at Austin, Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy.
Service
Director of TTP, the Targeted Therapeutic Drug Discovery & Development Program.
Director of the University of Texas at Austin, College of Pharmacy Pharm.D. Honors Program and Pharm.D. Ph.D. Concurrent Program.
Degree-Granting Education
1989-1992 The University of Cambridge, Cambridge, England, Doctor of Philosophy, Chemistry.
1985-1989 The University of Leeds, England, BSc, Chemistry.
Postgraduate Training
1994-1997 Postdoctoral Fellowship, The University of Dundee, Medical research Council Protein Phosphorylation Unit, Dundee, Scotland.
1992-1994 Postdoctoral Fellow, Brandeis University, Graduate Deparment of Biochemistry, Waltham, Ma, USA.
Pharm.D. students looking for educational stimulation and challenge beyond the traditional curriculum are invited to participate in the College’s Honors Program. This selective program challenges participants by introducing them to new ideas and placing them in contact with others of similar aptitude. Honors Program students participate in research projects with faculty mentors, and present their results at college seminars. Many of these students also present their results at national meetings and in peer-reviewed journal articles.
The college offers a sequential Pharm.D./Ph.D. degree track program to qualified pharmacy students. This program combines the features of a professional Pharm.D. degree with the advanced training and research of a pharmaceutical sciences Ph.D. degree. The areas of emphasis of the program are: Chemical Biology and Medicinal Chemistry, Pharmacology and Toxicology, and Pharmaceutics.
Our research program focuses on two areas under the theme of cancer cell signaling and therapeutics. We emphasize an understanding of the cellular and biochemical properties of signaling proteins, to determine how they are regulated, how they perform their functions and as a basis for designing novel therapeutic strategies to target human cancers.
1) Molecular mechanisms of signal transduction. The altered regulation and function of signaling proteins, such as protein kinases, contribute to the ability of tumors to form and then to grow. Altered signaling also helps cancer cells to survive severe stresses that result from such things as poor oxygenation, altered metabolism and genetic instability. In addition, aberrant signaling allows cancer cells to avoid the immune system and promotes tumor metastasis. Our work aims to better understand how changes that may occur to alter a protein’s expression, regulation or sequence facilitate cancer phenotypes.
2) Novel strategies to inhibit aberrant signaling in cancer cells. Drug discovery projects in the laboratory focus on either unique targets or alternative approaches to inhibit validated targets. They may involve assay development, structure-guided chemical synthesis of lead compounds and target validation. Special emphasis is placed on potential mechanisms of resistance.
The mitogen-activated protein kinases (MAPKs)
The mitogen-activated protein kinases (MAPKs) are ubiquitous and highly conserved elements of signaling pathways that control many cellular events essential for life, ranging from cellular programs (in the form of differentiation, proliferation, and death, amongst others) to rapid changes required for vital hormonal responses and homeostasis.
To achieve their regulatory roles, the human MAPKs mediate networks of signal transduction cascades that negotiate cellular responses to a diverse range of stimuli, including growth factors, irradiation, pro-inflammatory cytokines, and stresses.
A huge amount of evidence shows the loss of MAPK regulation to be associated with many debilitating diseases, including nearly all cancers neurological diseases such as Alzheimer disease, and inflammatory diseases.
Our interests in the MAPKs are the following:
Mechanisms of catalysis: fundamental knowledge of the enzymatic mechanisms that underlie how proteins evolve to be substrates for MAP kinases is obscure. We study the mechanisms of substrate phosphorylation by MAPKs in vitro and in cells. Knowledge of these mechanism aid in the design of MAPK inhibitors, as well as in the understanding of their cellular signaling mechanisms and specificity.
Ets-1 docks onto ERK2 using two remote non-canonical docking interactions. The docking generates an ensemble of conformations of the still dynamic phospho-acceptor near the ERK2 active site. This ensemble comprises of states in which the phospho-acceptor and surrounding regions (including the Pro in the P+1 position) are in appropriate conformation (along with the catalytic elements of ERK2) for chemistry (high-activity state), and those in which they are not (low-activity state). In principle, this could involve multiple states of varying inherent activity. Systems that substantially populate the states of high-activity are efficiently phosphorylated. We are interested in understanding MAPK specificity in the general context of this model.
Regulation and cellular functions of MAPK isoforms:We study how MAPK isoforms are regulated and investigate isoform-specific signaling pathways. Knowledge of these processes help us define isoform-specific functions in human cancers, which we hope will provide opportunities for new therapeutic modalities.
Inhibitors: through our biochemical studies we have identified novel inhibitors of ERK. Our hope is to develop potent inhibitors, which can overcome common mechanisms of resistance observed for current ERK pathway inhibitors that are in the clinic
Biomarkers: Currently, there is a lack of reliable technology to quantify MAPKs isolated from human tissue, which is essential for understanding their functions. We have created a MAPK array that we will optimize to quantitate the activity of human MAPK isoforms. Our goal is to establish a MAPK array as the basis for a new point-of-care assay guiding cancer treatment.
Elongation Factor 2 kinase
Protein synthesis (translation) constitutes one of the most fundamental of all cellular processes. The balance between protein synthesis and protein degradation is critical in maintaining cellular homeostasis. Translation is one of the most energy consumptive processes in a cell, accounting for as much as 30% of the energy usage in a eukaryotic cell, making its tight regulation a necessity.
Eukaryotic elongation factor 2 kinase (eEF-2K), a member of the atypical-kinase family, is a key regulator of the elongation phase of translation. eEF-2K phosphorylates and inactivates elongation factor 2 (eEF-2), leading to a reduction in global translation rates on one hand and differential translation of certain proteins on the other.
The activity of eEF-2K is dependent on calmodulin, and is subject to complex regulation by calcium ions and phosphorylation. It may also have cellular substrates other than eEF-2.
Our interests in eEF-2K are the following:
Regulation of eEF-2K: We are studying precisely how eEF-2K is activated and regulated. This information is critical to understanding its contributions to both normal cellular processes and in the etiology and progression of disease states. Toward this goal, we recently identified calmodulin-stimulated autophosphorylation on a specific residue, T348, as being the key step in the activation of eEF-2K and showed that phosphorylation of S500 potentiates the activation of eEF-2K by Ca-CaM.
Domain organization of eEF-2K. The N-terminus of eEF-2K (1-725, 82.2 kDa) comprises of a CaM binding domain (CBD, dark orange), and a catalytic kinase domain (KD, light blue). Autophosphorylation on T348 comprises a key step in the activation of eEF-2K. The C-terminus comprises of three predicted SEL1-like repeats (SLRs, purple). The disordered R-loop (located between the KD and SLRs) contains several phosphorylation sites including T348 and a regulatory site, S500.
