Matthew P Jacobson

Matthew P Jacobson
University of California, San Francisco | UCSF · Department of Pharmaceutical Chemistry

PhD

About

427
Publications
33,537
Reads
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16,137
Citations
Additional affiliations
September 1994 - August 1999
Massachusetts Institute of Technology
Position
  • PhD Student

Publications

Publications (427)
Article
Human epithelial 15-lipoxygenase-2 (h15-LOX-2, ALOX15B) is expressed in many tissues and has been implicated in atherosclerosis, cystic fibrosis and ferroptosis. However, there are few reported potent/selective inhibitors that are active ex vivo. In the current work, we report newly discovered molecules that are more potent and structurally distinc...
Article
The nuclear receptor-related 1 protein, Nurr1, is a transcription factor critical for the development and maintenance of dopamine-producing neurons in the substantia nigra pars compacta, a cell population that progressively loses the ability to make dopamine and degenerates in Parkinson's disease. Recently, we demonstrated that Nurr1 binds directly...
Preprint
The nuclear receptor-related protein, Nurr1, is a transcription factor critical for the development and maintenance of dopamine-producing neurons in the substantia nigra pars compacta, a cell population that progressively loses the ability to make dopamine and degenerates in Parkinson's disease. Recently, we demonstrated that Nurr1 binds directly t...
Article
Full-text available
The unfolded protein response (UPR) maintains protein folding homeostasis in the endoplasmic reticulum (ER). In metazoan cells, the Ire1 branch of the UPR initiates two functional outputs—non-conventional mRNA splicing and selective mRNA decay (RIDD). By contrast, Ire1 orthologs from Saccharomyces cerevisiae and Schizosaccharomyces pombe are specia...
Article
Small molecule colloidal aggregates adsorb and partially denature proteins, inhibiting them artifactually. Oddly, this inhibition is typically time-dependent. Two mechanisms might explain this: low concentrations of the colloid and enzyme might mean low encounter rates, or colloid-based protein denaturation might impose a kinetic barrier. These two...
Article
It was previously shown that human platelet 12S-lipoxygenase (h12-LOX) exists as a dimer; however, the specific structure is unknown. In this study, we create a model of the dimer through a combination of computational methods, experimental mutagenesis, and hydrogen-deuterium exchange (HDX) investigations. Initially, Leu183 and Leu187 were replaced...
Article
Full-text available
Despite a remarkable increase in the genomic profiling of cancer, integration of genomic discoveries into clinical care has lagged behind. We report the feasibility of rapid identification of targetable mutations in 153 pediatric patients with relapsed/refractory or high-risk leukemias enrolled on a prospective clinical trial conducted by the LEAP...
Article
Glycosaminoglycans (GAGs) such as heparan sulfate and chondroitin sulfate decorate all mammalian cell surfaces. These mucopolysaccharides act as coreceptors for extracellular ligands, regulating cell signaling, growth, proliferation, and adhesion. In glioblastoma, the most common type of primary malignant brain tumor, dysregulated GAG biosynthesis...
Article
The oxylipins, 5S,12S-dihydroxy-6E,8Z,10E,14Z-eicosatetraenoic acid (5S,12S-diHETE) and 5S,15S-dihydroxy-6E,8Z,11Z,13E-eicosatetraenoic acid (5S,15S-diHETE), have been identified in cell exudates and have chemotactic activity toward eosinophils and neutrophils. Their biosynthesis has been proposed to occur by sequential oxidations of arachidonic ac...
Article
Full-text available
Noninvasive methods to study glucocorticoid receptor (GR) signaling are urgently needed to elaborate the complexity of GR signaling in normal physiology and human disorders, as well as to identify selective GR modulators to treat diseases. Here, we report evidence supporting translational studies with (±)-11C-5-(4-fluorobenzyl)-10-methoxy-2,2,4-tri...
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The two oxylipins 7S,14S-dihydroxydocosahexaenoic acid (-diHDHA) and 7S,17S-diHDHA (resolvin D5 [RvD5]) have been found in macrophages and infectious inflammatory exudates and are believed to function as specialized pro-resolving mediators (SPMs). Their biosynthesis is thought to proceed through sequential oxidations of docosahexaenoic acid (DHA) b...
Article
Human reticulocyte 15-lipoxygenase-1 (h15-LOX-1 or ALOX15) and platelet 12-lipoxygenase (h12-LOX or ALOX12) catalysis of docosahexaenoic acid (DHA) and the maresin precursor, 14S-hydroperoxy-4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoic acid (14S-HpDHA), were investigated to determine their product profiles and relative rates in the biosynthesis of the key...
Preprint
Full-text available
The oxylipins, 7S,14S-diHDHA and 7S,17S-diHDHA (RvD5), have been found in macrophages exudates and are believed to function as specialized pro-resolving mediators (SPMs). Their biosynthesis is thought to proceed through sequential oxidations of docosahexaenoic acid (DHA) by lipoxygenase enzymes, specifically by h5-LOX first to 7S-HDHA, followed by...
Article
Full-text available
The progressive failure of protein homeostasis is a hallmark of aging and a common feature in neurodegenerative disease. As the enzymes executing the final stages of autophagy, lysosomal proteases are key contributors to the maintenance of protein homeostasis with age. We previously reported that expression of granulin peptides, the cleavage produc...
Article
KIT is a type-3 receptor tyrosine kinase that is frequently mutated at exon 11 or 17 in a variety of cancers. First-generation KIT tyrosine kinase inhibitors (TKI) are ineffective against KIT exon 17 mutations, which favor an active conformation that prevents these TKIs from binding. The ATP-competitive inhibitors, midostaurin and avapritinib, whic...
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Full-text available
Progranulin (PGRN) is an evolutionarily conserved glycoprotein associated with several disease states, including neurodegeneration, cancer and autoimmune disorders. This protein has recently been implicated in the regulation of lysosome function, whereby PGRN may bind to and promote the maturation and activity of the aspartyl protease cathepsin D (...
Article
Human immunodeficiency virus-1 viral infectivity factor (Vif) is an intrinsically disordered protein responsible for the ubiquitination of the APOBEC3 (A3) antiviral proteins. Vif folds when it binds Cullin-RING E3 ligase 5 and the transcription cofactor CBF-β. A five-protein complex containing the substrate receptor (Vif, CBF-β, Elongin-B, Elongin...
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Full-text available
Tau, a member of the MAP2/tau family of microtubule-associated proteins, stabilizes and organizes axonal microtubules in healthy neurons. In neurodegenerative tauopathies, tau dissociates from microtubules and forms neurotoxic extracellular aggregates. MAP2/tau family proteins are characterized by three to five conserved, intrinsically disordered r...
Article
Nurr1, a nuclear receptor essential for the development, maintenance, and survival of midbrain dopaminergic neurons, is a potential therapeutic target for Parkinson's disease, a neurological disorder characterized by the degeneration of these same neurons. Efforts to identify Nurr1 agonists have been hampered by the recognition that it lacks severa...
Article
Protein kinase CK2 has emerged as an attractive cancer therapeutic target. Previous studies have highlighted the challenge of optimizing CK2 ATP-competitive inhibitors that have low druggability due to their polycyclic ring scaffolds. Therefore the development of novel inhibitors with non-polycyclic scaffolds emerges as a promising strategy for dru...
Article
Human platelet hALOX12 (hALOX12 or h12-LOX) has been implicated in a variety of human diseases. The present study investigates the active site of hALOX12 to more thoroughly understand how it positions the substrate and achieves nearly perfect regio- and stereo-specificities (i.e., 100 +/- 5% of the 12(S)-hydroperoxide product), utilizing site-direc...
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Full-text available
Sodium-dependent glucose transporters (SGLTs) exploit sodium gradients to transport sugars across the plasma membrane. Due to their role in renal sugar reabsorption, SGLTs are targets for the treatment of type 2 diabetes. Current therapeutics are phlorizin derivatives that contain a sugar moiety bound to an aromatic aglycon tail. Here, we develop s...
Preprint
Full-text available
Tau, a member of the MAP2/tau family of microtubule-associated proteins, functions to stabilize and organize axonal microtubules in healthy neurons. In contrast, tau dissociates from microtubules and forms neurotoxic extracellular aggregates in neurodegenerative tauopathies. MAP2/tau family proteins are characterized by three to five conserved, int...
Article
Protein kinase CK2 is considered as an emerging target in cancer therapy, and recent efforts have been made to develop its ATP‐competitive inhibitors, but achieving selectivity with respect to related kinases remains challenging because of the highly conserved ATP‐binding pocket of kinases. Non‐ATP competitive inhibitors might solve this challenge;...
Preprint
Full-text available
Nurr1, a nuclear receptor essential for the development, maintenance, and survival of midbrain dopaminergic neurons, is a potential therapeutic target for Parkinson's disease, a neurological disorder characterized by the degeneration of these same neurons. Efforts to identify Nurr1 agonists have been hampered by the recognition that it lacks severa...
Article
Cancer cells rely on the chaperone, heat shock protein 70 (Hsp70), for survival and proliferation. Recently, benzothiazole-rhodacyanines have been shown to bind an allosteric site on Hsp70, interrupting its binding to nucleotide-exchange factors (NEFs) and promoting cell death in breast cancer cell lines. However, proof-of-concept molecules, such a...
Article
Full-text available
Chordoid glioma is a rare brain tumor thought to arise from specialized glial cells of the lamina terminalis along the anterior wall of the third ventricle. Despite being histologically low-grade, chordoid gliomas are often associated with poor outcome, as their stereotypic location in the third ventricle makes resection challenging and efficacious...
Article
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Protein-protein interactions (PPIs) are an important category of putative drug targets. Improvements in high throughput screening (HTS) have significantly accelerated the discovery of inhibitors for some categories of PPIs. However, methods suitable for screening multi-protein complexes (e.g. those composed of three or more different components) ha...
Article
Full-text available
The functions of most proteins are yet to be determined. The function of an enzyme is often defined by its interacting partners, including its substrate and product, and its role in larger metabolic networks. Here, we describe a computational method that predicts the functions of orphan enzymes by organizing them into a linear metabolic pathway. Gi...
Data
Benchmark pathways. Three well characterized pathways were used for benchmarking of the integrative pathway mapping: glycolysis (10 enzymes) (Kalyanaraman and Jacobson, 2010), cytidine monophosphate 3-deoxy-D-manno-octulosonate 8-phosphate (CMP KDO-8P) biosynthesis (four enzymes), and serine biosynthesis (five enzymes).
Data
Structural models for virtual screening and chemical transformations of proteins in L-gulonate catabolic pathway.
Data
Substrate and product ranks by enzyme using virtual screening and integrative pathway mapping for benchmark and prospective pathway construction. The number of candidate ligands as input is 3650 for the L-gulonate catabolic pathway. The ranks from individual docking runs are determined by docking score for an enzyme. The ranks by the integrative ap...
Data
DSF screening of a library of 189 compounds (Vetting et al., 2015) indicating ligands that stabilized thermal denaturation of SBPs. The ΔTm for each ligand was calculated as the difference of the Tm values measured with a ligand and without ligand for SBS from Haemophilus influenzae RdAW and Mannheimia haemolytica PHL213 (GulP: 82% sequence identit...
Data
Genetic deletion mutants of the putative L-gulonate catabolism pathway in H. influenzae Rd KW20 were generated with the following oligonucleotide sequences.
Data
qRT-PCR oligonucleotide sequences used for gene expression profiling.
Data
Structural models for virtual screening and chemical transformations of enzymes in benchmark pathways.
Data
Primer sequences used for cloning genes in L-gulonate catabolic pathway.
Article
The chemokine receptor CXCR7 is an attractive target for a variety of diseases. While several small molecule modulators of CXCR7 have been reported, peptidic macrocycles may provide advantages in terms of potency, selectivity, and reduced off-target activity. We produced a series of peptidic macrocycles that incorporate an N-linked peptoid function...
Article
Resistance to clinical antiandrogens has plagued the evolution of effective therapeutics for advanced prostate cancer. As with the first-line therapeutic bicalutamide (Casodex), resistance to newer antiandrogens (enzalutamide, ARN-509) develops quickly in patients, despite the fact that these drugs have ~10-fold better affinity for androgen recepto...
Article
Full-text available
Central nervous system (CNS) chemical protection depends upon discrete control of small-molecule access by the blood-brain barrier (BBB). Curiously, some drugs cause CNS side-effects despite negligible transit past the BBB. To investigate this phenomenon, we asked whether the highly BBB-enriched drug efflux transporter MDR1 has dual functions in co...
Article
The intracellular pH (pHi) of most cancers is constitutively higher than that of normal cells and enhances proliferation and cell survival. We found that increased pHi enabled the tumorigenic behaviors caused by somatic arginine-to-histidine mutations, which are frequent in cancer and confer pH sensing not seen with wild-type proteins. Experimental...
Article
Full-text available
Cancer can be viewed as a set of different diseases with distinctions based on tissue origin, driver mutations, and genetic signatures. Accordingly, each of these distinctions have been used to classify cancer subtypes and to reveal common features. Here, we present a different analysis of cancer based on amino acid mutation signatures. Non-negativ...
Data
Six nonsynonymous mutation signatures identified by NMF on individual samples. NMF identifies six mutation signatures from individual samples (only those with >10 total nonsynonymous mutations) including four signatures (A), (B), (C), (D) identified in the aggregated analysis and two other complex signatures, (E) and (F). Amino acid mutations to or...
Data
Six nonsynonymous mutation signatures identified by NMF on aggregated data. NMF identifies six mutation signatures from data aggregated by cancer subtype including signatures with (A) high R>H weights, (B) high A>T and R>H weights, (C) high E>K weights, (D) high E>K and E>Q weights, and complex signatures (E) and (F). Amino acid mutations to or fro...
Data
Principal components analysis loadings on aggregated nonsynonymous mutations for the first two principal components. (A) The first principal component separates cancers with many R>H mutations from those with many E>K mutations, and (B) the second principal component separates these cancers from those with more complex signatures. Amino acid mutati...
Data
Six nonsynonymous mutation signatures identified by NMF on individual samples from the COSMIC database. Six mutation signatures identified by NMF from individual samples in the COSMIC database (only those with >10 total nonsynonymous mutations) used for validation of NMF results from Alexandrov data. Amino acid mutations to or from X represent muta...
Data
Expected and observed mutation frequency for cancer driver genes. All Filters: entire filtering schema (Alexandrov et al., 2013) applied; No Filtering: none of the filters applied; Seq. Artifact Filter: only mutations defined as sequencing artifacts (Alexandrov et al., 2013) filtered. The expected range of mutation counts for the driver genes in ca...
Data
Total nonsynonymous mutation counts by cancer type. Data was filtered using sequencing artifacts filter and any samples containing only synonymous mutations were eliminated from analysis (see Methods). Calculated is the mean number of nonsynonymous mutations per sample. Pilocytic astrocytoma samples were eliminated from analyses due to low frequenc...
Preprint
Full-text available
Cancer can be viewed as a set of different diseases with distinctions based on tissue origin, driver mutations, and genetic signatures. Accordingly, each of these distinctions have been used to classify cancer subtypes and to reveal common features. Here, we present a different analysis of cancer based on amino acid mutation signatures. Non-negativ...
Article
Full-text available
Nicotinic acid adenine dinucleotide phosphate (NAADP) and cyclic ADP-ribose (cADPR) are Ca(2+)-mobilizing messengers important for modulating cardiac excitation-contraction coupling and pathophysiology. CD38, which belongs to the ADP-ribosyl cyclase (ARC) family, catalyzes synthesis of both NAADP and cADPR in vitro However, it remains unclear wheth...
Preprint
Optimal brain function depends upon efficient control over the brain entry of blood components; this is provided by the blood-brain barrier (BBB). Curiously, some brain-impermeable drugs can still cause behavioral side effects. To investigate this phenomenon, we asked whether the promiscuous drug efflux transporter Mdr1 has dual functions in transp...
Article
Macrocycles are appealing drug candidates due to their high-affinity, specificity, and favorable pharmacological properties. In this study, we explored the effects of chemical modifications to a natural product macrocycle upon its activity, 3D geometry, and conformational entropy. We chose thiocillin as a model system, a thiopeptide in the ribosoma...
Article
Full-text available
We report the discovery of a new potent allosteric effector of sickle cell hemoglobin, GBT440 (36), that increases the affini-ty of hemoglobin for oxygen and consequently inhibits its polymerization when subjected to hypoxic conditions. Unlike earlier allosteric activators that bind covalently to hemoglobin in a 2:1 stoichiometry, 36 binds with a 1...
Article
Macrocycles pose challenges for computer-aided drug design due to their conformational complexity. One fundamental challenge is identifying all low-energy conformations of the macrocyclic ring, which is important for modeling target binding, passive membrane permeation, and other conformation-dependent properties. Macrocyclic polyketides are medica...
Article
Full-text available
AMPA-type glutamate receptors (AMPARs) mediate fast excitatory neurotransmission and predominantly assemble as heterotetramers in the brain. Recently, the crystal structures of homotetrameric GluA2 demonstrated that AMPARs are assembled with two pairs of conformationally distinct subunits, in a dimer of dimers formation. However, the structure of h...