Kevin Dalby

Kevin Dalby
University of Texas at Austin | UT · Division of Chemical Biology & Medicinal Chemistry

Professor
Collaborate with The Targeted Therapeutic Drug Discovery & Development Program (TTP) http://sites.utexas.edu/ttdddp/

About

228
Publications
59,778
Reads
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8,435
Citations
Introduction
Dr. Kevin Dalby UT-Austin (Twitter @KevinNDalby) is a professor of chemical biology and medicinal chemistry in the College of Pharmacy, and Department of Oncology at The University of Texas in Austin. He studies mechanisms of cell signaling to develop targeted therapeutics. Dr. Dalby's research areas include biochemistry, cancer, cell biology, chemical biology, drug discovery & diagnostics, and enzymology.
Additional affiliations
August 1997 - present
University of Texas at Austin
Position
  • Professor
Description
  • Dr. Dalby studies mechanisms of cell signaling to develop targeted therapeutics. Research areas include biochemistry, cancer, cell biology, chemical biology, drug discovery & diagnostics, and enzymology. Dr. Dalby is the director of The Targeted Therapeutic Drug Discovery & Development Program (TTP) http://sites.utexas.edu/ttdddp/people/kevin-n-dalby/. The Dalby laboratory is developing a small molecule screening program to identify strategies and lead compounds to address COVID-19.
May 1994 - May 1997
University of Dundee
Position
  • PostDoc Position
Description
  • Delineated the mechanism of activation of p90RSK by ERK Identification of regulatory phosphorylation sites in mitogen-activated protein kinase (MAPK)-activated protein kinase-1a/p90rsk that are inducible by MAPK JBC 1998 273 1496-505
May 1992 - May 1994
Brandeis University
Position
  • PostDoc Position
Description
  • Physical organic chemistry Lifetimes of Imidium Ions in Aqueous Solution JACS 1997 119 77171-7280 General acid catalysis of the reversible addition of thiolate anions to cyanamide Perkin Transactions 2, 1997 8 1555-1564
Education
October 1988 - May 1992
University of Cambridge
Field of study
  • Organic Chemistry
October 1985 - June 1988
University of Leeds
Field of study
  • Chemistry

Publications

Publications (228)
Article
Full-text available
Eukaryotic elongation factor 2 kinase (eEF-2K) is an atypical protein kinase regulated by Ca(2+) and calmodulin (CaM). Its only known substrate is eukaryotic elongation factor 2 (eEF-2), whose phosphorylation by eEF-2K impedes global protein synthesis. To date, the mechanism of eEF-2K autophosphorylation has not been fully elucidated. To investigat...
Article
Full-text available
Calmodulin (CaM)-dependent eukaryotic elongation factor 2 kinase (eEF-2K) impedes protein synthesis through phosphorylation of eukaryotic elongation factor 2 (eEF-2). It is subject to complex regulation by multiple upstream signaling pathways, through poorly described mechanisms. Precise integration of these signals is critical for eEF-2K to approp...
Article
Full-text available
Recently, the targeting of ERK with ATP-competitive inhibitors has emerged as a potential clinical strategy to overcome acquired resistance to BRAF and MEK inhibitor combination therapies. In this study, we investigate an alternative strategy of targeting the D-recruitment site (DRS) of ERK. The DRS is a conserved region that lies distal to the act...
Preprint
Full-text available
The SARS-CoV-2 spike (S) protein is a critical component of subunit vaccines and a target for neutralizing antibodies. Spike is also undergoing immunogenic selection with clinical variants that increase infectivity and partially escape convalescent plasma. Here, we describe spike display, a high-throughput platform to rapidly characterize glycosyla...
Article
Full-text available
Arrestins were first discovered as suppressors of G protein-mediated signaling by G protein-coupled receptors. It was later demonstrated that arrestins also initiate several signaling branches, including mitogen-activated protein kinase cascades. Arrestin-3-dependent activation of the JNK family can be recapitulated with peptide fragments, which ar...
Article
To identify novel inhibitors of the carbapenemase New Delhi metallo-β-lactamase (NDM) as possible therapeutic compounds, we conducted a high-throughput screen of a 43,358-compound library. One of these compounds, a 2-quinazolinone linked through a diacylhydrazine to a phenyl ring (QDP-1) (IC50 = 7.9 ± 0.5 μM), was characterized as a slow-binding re...
Preprint
Older people have been disproportionately vulnerable to the current SARS-CoV-2 pandemic, with an increased risk of severe complications and death compared to other age groups. A mix of underlying factors has been speculated to give rise to this differential infection outcome, including changes in lung physiology, weakened immunity, and severe immun...
Article
Background: Triple-negative breast cancer (TNBC) has high rates of relapse and metastasis. It has a high proportion of cancer stem-like cells (CSCs), which possess self-renewal and tumor initiation capacity. MELK (maternal embryonic leucine zipper kinase), a protein kinase of the Snf1/AMPK kinase family, plays a critical role in promoting CSC maint...
Article
Full-text available
The combination of ultrahigh-throughput screening and sequencing informs on function and intragenic epistasis within combinatorial protein mutant libraries. Establishing a droplet-based, in vitro compartmentalised approach for robust expression and screening of protein kinase cascades (>10 ⁷ variants/day) allowed us to dissect the intrinsic molecul...
Chapter
The luminescence method measures the spontaneous emission of a photon by a substance. Among the various types of luminescence, fluorescence and chemiluminescence are the most dominant methods used in high throughput screening (HTS) campaigns due to their keen sensitivity, broad linearity, robustness, and flexible automation/miniaturization. Fluores...
Article
Arrestin binding to active phosphorylated G protein-coupled receptors terminates G protein coupling and initiates another wave of signaling. Among the effectors that bind directly to receptor-associated arrestins are extracellular signal-regulated kinases 1/2 (ERK1/2), which promote cellular proliferation and survival. Arrestins may also engage ERK...
Preprint
Full-text available
Translation is a highly energy consumptive process tightly regulated for optimal protein quality and adaptation to energy and nutrient availability. A key facilitator of this process is the α-kinase eEF-2K that specifically phosphorylates the GTP-dependent translocase eEF-2, thereby reducing its affinity for the ribosome and suppressing the elongat...
Article
Full-text available
The SARS-CoV-2 spike protein is a critical component of vaccines and a target for neutralizing monoclonal antibodies (nAbs). Spike is also undergoing immunogenic selection with variants that increase infectivity and partially escape convalescent plasma. Here, we describe Spike Display, a high-throughput platform to rapidly characterize glycosylated...
Article
Src kinase activity controls diverse cellular functions, including cell growth, migration, adhesion, and survival. It is de-regulated in several cancers, including breast cancer, where it is highly expressed and phosphorylated. Thus, targeting Src by a small molecule is a feasible strategy for managing different breast cancer types. Several Src kin...
Article
Full-text available
Luminescence is characterized by the spontaneous emission of light resulting from either chemical or biological reactions. Because of their high sensitivity, reduced background interference, and applicability to numerous situations, luminescence-based assay strategies play an essential role in early-stage drug discovery. Newer developments in lumin...
Article
Background Although an immunosuppressive tumor microenvironment (TME) is key for tumor progression, the molecular characteristics associated with the immunosuppressive TME remain unknown in triple-negative breast cancer (TNBC). Our previous functional proteomic study of TNBC tumors identified that C-JUN N-terminal kinase (JNK) pathway–related molec...
Article
Full-text available
The calmodulin (CaM) activated α-kinase, eukaryotic elongation factor 2 kinase (eEF-2 K), plays a central role in regulating translational elongation by phosphorylating eukaryotic elongation factor 2 (eEF-2), thereby reducing its ability to associate with the ribosome and suppressing global protein synthesis. Using TR (for truncated), a minimal fun...
Article
Full-text available
Cancer cells are a major source of enzymes that modify collagen to create a stiff, fibrotic tumor stroma. High collagen lysyl hydroxylase 2 (LH2) expression promotes metastasis and is correlated with shorter survival in lung adenocarcinoma (LUAD) and other tumor types. LH2 hydroxylates lysine (Lys) residues on fibrillar collagen’s amino- and carbox...
Article
Full-text available
Amplification‐independent c‐MYC overexpression is suggested in multiple cancers. Targeting c‐MYC activity has therapeutic potential, but efforts thus far have been mostly unsuccessful. To find a druggable target to modulate c‐MYC activity in cancer, we identified two kinases, MAPKAPK2 (MK2) and the DNA‐dependent protein kinase catalytic subunit (DN...
Preprint
Full-text available
Three pathogenic human coronaviruses have emerged, with SARS-2 causing a global pandemic. While therapeutic antibodies targeting the SARS-2 spike currently focus on the poorly conserved receptor-binding domain, targeting essential neutralizing epitopes on the more conserved S2 domain may provide broader protection. We report three antibodies bindin...
Conference Paper
Immune checkpoint inhibitors (ICIs) is now a standard of care for metastatic TNBC, the most aggressive subtype of breast cancer. However, rates of tumor response to ICIs are low. Evidence suggests that an immunosuppressive TME weakens the efficacy of ICIs. We previously showed that JNKs can regulate migration, invasion, and stemness of TNBC, and JN...
Conference Paper
The expeditious quantification of signalling in complex biological system by novel technologies will aid in the development of biological models, help to identify targets for treatment, and assess treatment plans. The biochemical process of protein phosphorylation, which underlies almost all aspects of cell signaling, is typically evaluated by immu...
Chapter
Full-text available
Extracellular signal–regulated kinase (ERK) is a mitogen-activated protein kinase (MAPK) that mediates cellular processes such as proliferation, differentiation, cell motility, and survival. Dysregulation of the ERK signaling pathway is believed to have a protumorigenic role in many cancers, and studies also implicate it in a variety of other proli...
Article
Full-text available
Hypoxic solid tumors induce the stabilization of hypoxia-inducible factor 1 alpha (HIF1α), which stimulates the expression of many glycolytic enzymes and hypoxia-responsive genes. A high rate of glycolysis supports the energetic and material needs for tumors to grow. Fructose-1,6-bisphosphate aldolase A (ALDOA) is an enzyme in the glycolytic pathwa...
Article
Full-text available
Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer characterized by metastasis, drug resistance and high rates of recurrence. With a lack or targeted therapies, TNBC is challenging to treat and carries a poor prognosis. Patients with TNBC tumors expressing high levels of ERK2 have a poorer prognosis than those with low ERK2...
Article
Full-text available
Ultraviolet photodissociation (UVPD) has emerged as a promising tool to characterize proteins with regard to not only their primary sequences and post-translational modifications, but also their tertiary structures. In this study, three metal-binding proteins, staphylococcal nuclease, azurin, and calmodulin, are used to demonstrate the use of UVPD...
Article
Full-text available
C-JUN N-terminal kinases (JNKs), which belong to the mitogen-activated protein kinase (MAPK) family, are evolutionarily conserved kinases that mediate cell responses to various types of extracellular stress insults. They regulate physiological processes such as embryonic development and tissue regeneration, playing roles in cell proliferation and p...
Article
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Here, we developed a coralyne-based, 'light-up' intercalator displacement assay to identify molecular stabilizers of triplex DNA using a sequence from a chromosomal breakpoint hotspot in the human c-MYC oncogene. Its...
Article
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The understanding of complex biological systems requires an ability to evaluate interacting networks of genes, proteins, and cellular reactions. Enabling technologies that support the rapid quantification of these networks will facilitate the development of biological models, help to identify treatment targets, and assess treatment plans. The bioch...
Article
Constitutive activation of STAT3 can play a vital role in the development of melanoma. STAT3-targeted therapeutics are reported to show efficacy in melanomas harboring the BRAFV600E mutant and also in vemurafenib-resistant melanomas. We designed and synthesized a series of substituted nitric oxide (NO)-releasing quinolone-1,2,4-triazole/oxime hybri...
Article
Full-text available
Eukaryotic elongation factor 2 kinase (eEF‐2 K) regulates protein synthesis by phosphorylating eukaryotic elongation factor 2 (eEF‐2), thereby reducing its affinity for the ribosome and suppressing global translational elongation rates. eEF‐2 K is regulated by calmodulin (CaM) through a mechanism that is distinct from that of other CaM‐regulated ki...
Article
Cover Caption: The cover image is based on the In Perspective Targeting ERK beyond the boundaries of the kinase active site in melanoma by Rachel M. Sammons et al., DOI 10.1002/mc.23047.
Article
Full-text available
Regions of genomic instability are not random and often co-localize with DNA sequences that can adopt alternative DNA structures (i.e. non-B DNA, such as H-DNA). Non-B DNA-forming sequences are highly enriched at translocation breakpoints in human cancer genomes, representing an endogenous source of genetic instability. However, a further understan...
Conference Paper
Mutations in pathways that enhance the activity of ERK1 and ERK2 are frequently present in human cancers, reflecting their important roles in tumor initiation, and progression. This notion is reinforced by observations in BRAF V600E mutant melanoma where the majority of the mechanisms of resistance to FDA-approved combination therapies targeting BR...
Conference Paper
Breast cancer is the most prevalent type of cancer among women. Triple negative breast cancer (TNBC) is a highly aggressive and heterogeneous subtype of breast cancer. It is the most challenging subtype to treat mainly due its aggressive nature and lack of targets such as HER2 (human epidermal growth factor 2), PR (progesterone receptor), and ER (e...
Article
Breast cancer is the most prevalent type of cancer among women. Triple negative breast cancer (TNBC) is a highly aggressive and heterogeneous subtype of breast cancer. It is the most challenging subtype to treat mainly due its aggressive nature and lack of targets such as HER2 (human epidermal growth factor 2), PR (progesterone receptor), and ER (e...
Article
Maternal embryonic leucine-zipper kinase (MELK) overexpression impacts survival and proliferation of multiple cancer types, most notably glioblastomas and breast cancer. This makes MELK an attractive molecular target for cancer therapy. Yet the molecular mechanisms underlying the involvement of MELK in tumorigenic processes are unknown. MELK partic...
Conference Paper
p>Breast cancer is the most prevalent type of cancer among women. Triple negative breast cancer (TNBC) is a highly aggressive and heterogeneous subtype of breast cancer. It is the most challenging subtype to treat mainly due its aggressive nature and lack of targets such as HER2 (human epidermal growth factor 2), PR (progesterone receptor), and ER...
Conference Paper
Mutations in pathways that enhance the activity of ERK1 and ERK2 are frequently present in human cancers, reflecting their important roles in tumor initiation, and progression. This notion is reinforced by observations in BRAF V600E mutant melanoma where the majority of the mechanisms of resistance to FDA-approved combination therapies targeting BR...
Conference Paper
The activity of protein kinases in biological samples is typically estimated by determining the phosphorylation status of either the kinase itself, or a known cellular substrate. This is typically evaluated by multi-step western blotting, or proteomics procedures. Such procedures typically provide qualitative estimates of the modifications in quest...
Article
Full-text available
Glycolytic enzyme fructose-bisphosphate aldolase A is an emerging therapeutic target in cancer. Recently, we have solved the crystal structure of murine aldolase in complex with naphthalene-2,6-diyl bisphosphate (ND1) that served as a template of the design of bisphosphate-based inhibitors. In this work, a series of ND1 analogues containing difluor...
Article
Full-text available
Extracellular signal‐regulated kinase 1/2 (ERK1/2) constitute a point of convergence for complex signaling events that regulate essential cellular processes, including proliferation and survival. As such, dysregulation of the ERK signaling pathway is prevalent in many cancers. In the case of BRAF‐V600E mutant melanoma, ERK inhibition has emerged as...
Article
Full-text available
The protein kinase MELK is an important kinase in cell signaling and has shown to be a promising anti-cancer target. Recent work has resulted in a novel small molecule scaffold targeting MELK, IN17. However, there has been little structural information or physical understanding of MELK-IN17 interactions. Using Tinker-OpenMM on GPUs, we have perform...
Article
Full-text available
Overexpression and activation of c-Jun-N-terminal kinases (JNK) have been observed in multiple cancer cell lines and tumor samples. Various JNK isoforms have been reported to promote lung and liver cancer, as well as keratinocyte transformation, suggesting an important role of JNK signaling in promoting tumor development. However, there are three J...
Article
Full-text available
Eukaryotic elongation factor 2 kinase (eEF-2K), an atypical calmodulin-activated protein kinase, regulates translational elongation by phosphorylating its substrate, eukaryotic elongation factor 2 (eEF-2), thereby reducing its affinity for the ribosome. The activation and activity of eEF-2K are critical for survival under energy-deprived conditions...
Article
Full-text available
Iron is an essential requirement for the survival and virulence for bacteria. The bacterial ferrous iron transporter protein B (FeoB) functions as a major iron transporter in prokaryotes and has an N-terminal domain (NFeoB) with homology to eukaryotic G-proteins. Its GTPase activity is required for ferrous iron uptake, making it a potential target...
Article
Approximately 60% of human cancers exhibit enhanced activity of ERK1 and ERK2, reflecting their multiple roles in tumor initiation and progression. Acquired drug resistance, especially mechanisms associated with the reactivation of the MAPK (RAF/MEK/ERK) pathway represent a major challenge to current treatments of melanoma and several other cancers...
Article
Full-text available
A large number of natural products containing the propellane scaffold have been reported to exhibit cytotoxicity against several cancers; however, their mechanism of action is still unknown. Anticancer drugs targeting DNA are mainly composed of small planar molecule/s that can interact with the DNA helix, causing DNA malfunction and cell death. The...
Article
Full-text available
Scaffold proteins tether and orient components of a signaling cascade to facilitate signaling. Although much is known about how scaffolds colocalize signaling proteins, it is unclear whether scaffolds promote signal amplification. Here, we used arrestin-3, a scaffold of the ASK1-MKK4/7-JNK3 cascade, as a model to understand signal amplification by...
Article
Full-text available
Lysyl hydroxylase-2 (LH2) catalyzes the hydroxylation of telopeptidyl lysine residues on collagen, leading to the formation of stable collagen cross-links that connect collagen molecules and stabilize the extracellular matrix. High levels of LH2 have been reported in the formation and stabilization of hydroxylysine aldehyde-derived collagen cross-l...