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The Chemical Biology Consortium (CBC) of the National Cancer Institute is a multi-institute consortium of academic and industrial partners dedicated to advancing novel cancer therapeutics. Arkin Lab and Renslo Lab, in conjunction with the Small Molecule Discovery Center (SMDC), have played a leadership role in the CBC since its inception in 2009. UCSF is a Dedicated Center in the CBC, and has contributed to six different projects, including P97/VCP and Taspase, which are both ongoing. The Consortium is especially supportive of the novel, cutting-edge techniques in the lab such as high-throughput biophysical screening and covalent tethering-based screening. Chemical synthesis is also leveraged to advance hit molecules and formulate tool compounds to further define the basic biology. To apply to have new programs enter the CBC pipeline, visit NExT: How to Apply: Overview.
The Tau Consortium is funded through the generosity of the Rainwater Charitable Foundation and is dedicated to the discovery of treatments of tau protein diseases (tauopathies). Media coverage of chronic traumatic encephalopathy (CTE) has brought increased awareness of the role of tau in neurodegenerative disease. In addition to CTE, accumulation of tau has been observed in Alzheimer’s disease, Pick’s disease, frontotemporal dementia, progressive supranuclear palsy, and traumatic brain injury. Tauopathies generally present as diseases of protein misfolding with aggregation of tau observed in neurons. SMDC scientists serve as strategic and operational coordinators of the drug discovery efforts in the Tau Consortium. Our team is also involved in two consortium programs to define the roles of acetylation and proteolysis of tau in disease processes.
The UCSF Helen Diller Family Comprehensive Cancer Center is a world-class center for patient treatment and for research into the causes, prevention, and treatments for cancer. The SMDC aims to become a Cancer Center core facility in the pending NIH Cancer Center Support Grant. If awarded, Cancer Center members will receive a discounted rate for using SMDC services for cancer research. The grant will also enable more cancer programs to enter hit-to-lead chemistry and will support screening of patient-derived materials for precision medicine initiatives.
The Accelerating Therapeutics for Opportunities in Medicine (ATOM) Consortium is a pre-competitive public-private partnership that aims to dramatically increase the speed and efficiency of drug discovery through the integration of high-performance computing, new approaches to characterize cancer biology, and emerging biotechnology capabilities. ATOM is a collaboration with the Frederick National Laboratory for Cancer Research (FNLCR) (on behalf of the National Cancer Institute), GSK, Lawrence Livermore National Laboratory (LLNL) (on behalf of the United States Department of Energy), and UCSF. SMDC Co-director Michelle Arkin serves on the ATOM Joint Research Committee and seeks the engagement of UCSF faculty in proposing cancer targets, designing state-of-the-art cellular models, and developing computational algorithms. Postdoctoral positions are available through NCI (see ATOM Fellowship Program FAQs) and the R&D Postdoctoral Global Training Program at GSK’s Postgraduate Opportunities.
As part of an HHMI Collaborative Innovation Award headed by Peter Walter, we conducted a series of cell-based luciferase reporter gene screens to probe the Unfolded Protein Response (UPR). The UPR is triggered when misfolded proteins accumulate in the endoplasmic reticulum. Homeostatic sensors and effectors result in the upregulation of protein folding machinery. Under prolonged stress or loss of control, however, the UPR can become a pathological survival system (cancer) or lead to apoptosis. The team discovered small molecules ISRIB (Sidrauski et al. 2013, Elife, 2:e00498) and CEAPIN (Gallagher et al. 2016, 5:e11878), both novel small molecules inhibitors of PERK and ATF6 pathways respectively, with therapeutic potential in cancer and neurodegenerative disorders. All three programs have been partnered with biotechnology companies (Genentech, Calico Labs). The Walter Lab and other researchers have made ISRIB a breakthrough tool to study the role of the cellular stress response in traumatic brain injury (TBI) and other diseases.
To fight neglected tropical diseases
Drug repurposing begins with known pharmaceutical compounds with a history of therapeutic use. Hence, there is a wealth of experimental and clinical data that helps to expedite the development of these drugs for new indications. Drug repurposing is particularly appealing for neglected tropical (parasitic) diseases (NTDs), where the existing drugs have multiple side effects or limited efficacy. One reason for drug repurposing for NTDs is that developing a drug from an existing drug is usually much less expensive, which is important for indications where there is little financial incentive. Second, since most drugs targets eukaryotes (e.g., humans or yeast), there may be a good scientific rationale for modulating similar biological processes in the parasitic organism.
We have collaborated with investigators from the Center for Discovery and Innovation in Parasitic Diseases (CDIPD) to develop high-throughput screens for parasites as diverse as the single-celled parasites Trypanosoma cruzi, Leishmania, T. brucei, Entamoeba histolytica, Giardia lamblia, and Cryptosporidium, to large parasitic worms Brugia and Schistosoma. In each case, existing drugs were found to be active in killing parasites while sparing the host. For example, in collaboration with the McKerrow Lab (UCSF) and Reed Lab (UCSD), we helped repurpose Auranofin, a rheumatoid arthritis drug from the 1950s, for the treatment of E. histolytica, the causative agent of amebiasis and amebic dysentery. The compound received FDA orphan drug status and has entered clinical trials for amebiasis and giardia (A high-throughput drug screen for Entamoeba histolytica identifies a new lead and target, Debnath, et al, 2012, Nature Medicine 18:956-960).
For NTD screens and chemical optimization, see also:
A screen against Leishmania intracellular amastigotes: comparison to a promastigote screen and identification of a host cell-specific hit. (De Muylder, et al, PLoS NTD 2011, 5:e1253)
Tetrafluorophenoxymethyl ketone cruzain inhibitors with improved pharmacokinetic properties as therapeutic leads for Chagas’ disease. (Neitz, et al, Bioorg Med Chem Lett 2015, 25:4834-7)
Quantification and clustering of phenotypic screening data using time-series analysis for chemotherapy of schistosomiasis. (Lee, et al, BMC Genomics 2012, 13:S4)
Mining a cathepsin inhibitor library for new antiparasitic drug leads. (Ang, et al, PLoS NTD 2011, 5:e1023)
Novel non-peptidic vinylsulfones targeting the S2 and S3 subsites of parasite cysteine proteases. (Bryant, et al, Bioorg Med Chem Lett 2009, 19:6218-21)
An image-based assay for high throughput screening of Giardia lamblia. (Gut, et al, J Microb Meth 2011, 83:398-405)
Lead identification to clinical candidate selection: drugs for Chagas disease. (Neitz, et al, J Biomol Screening 2015, 20:101-111)
Imaging-based screens for ciliogenesis and hedgehog signaling
Vertebrate Hedgehog (Hh) signals involved in development and some forms of cancer, such as basal cell carcinoma, are transduced by the primary cilium, a microtubule projection found on many cells. A critical step in vertebrate Hh signal transduction is the regulated movement of Smoothened (Smo), a seven-transmembrane protein, to the primary cilium. The Reiter Lab and the SMDC are working to identify small molecules that interfere with either the ciliary localization of Smo or ciliogenesis. Using high-throughput, microscopy-based screen for compounds that alter the ciliary localization of YFP-tagged Smo, we have identified several compounds that inhibit Hh pathway activity, either by binding directly to Smo or by blocking ciliogenesis. (Small molecule inhibitors of Smoothened ciliary localization and ciliogenesis, Wu, et al, Proc Natl Acad Sci, USA, 2012, 109; 13644-13649)
Glioblastoma (GBM) is a highly resistant brain cancer in both children and adults. Notable Labs aims to use patient-derived materials to better identify effective anticancer agents. Together, we developed an assay using neurospheres derived from GBM cell lines and surgical isolates. Bright-field microscopy and image analysis were used to measure the change in size of the tumor following treatment with compounds from the SMDC drug collection and other agents reported to kill glioblastoma cells.
Drug discovery in model organisms such as zebrafish is a promising approach for identifying biologically relevant lead compounds. As a new approach for Parkinson’s disease, Guo Lab has developed a model for dopaminergic (DA) neuron development in which nitroreductase (NTR) and an mCherry marker are selectively expressed in DA neurons. When zebrafish larvae are treated with the prodrug metronidazole (Mtz), the NTR within the neuron converts Mtz into a cytotoxin, causing cell type-specific ablation. If zebrafish brains can be visualized and measured in high-throughput, one could screen for compounds that protect DA neurons from degeneration or stimulate their regeneration. High-content imaging of zebrafish at cellular resolution is challenging, however, due to the difficulty in orienting larvae en masse such that the cell type of interest is in clear view. Working in collaboration, Guo Lab, Huang Lab, and SMDC discovered that using a liquid handler to quickly aspirate and replace 40uL of liquid in each well caused the anesthetized embryo in the wells to tumble and assume a new pose. Therefore, we were able to increase the chance of acquiring an image of a correctly posed larva by repeatedly re-posing and imaging the larvae. Overall, five cycles of imaging and re-posing took a total of 75 minutes per plate, allowing > 1,800 fish larvae to be analyzed per day. (A High-Content Larval Zebrafish Brain Imaging Method for Small Molecule Drug Discovery, Liu et al. PLoS One. 2016, 11(10):e0164645)
New ways of targeting Ras
In collaboration with the SMDC, UCSF investigators Kevan Shokat and Frank McCormick have produced exciting new avenues for inhibiting Ras and have figured significantly in a resurgent interest in this oncogene, long considered undruggable. Screening the oncogenic mutation G12C, the Shokat Lab discovered disulfide hits that were then converted to irreversible electrophilic lead compounds. Lead compounds were shown by X-ray crystallography to bind in an allosteric pocket beneath switch II and covalently engage Cys12. Related compounds are being developed in the drug candidates by Wellspring Biosciences. The McCormick Lab performed a tethering screen to identify compounds that label the C-terminal CAAX box cysteine in Ras, the site of protein prenylation. Selected disulfide hits that showed selectivity for the CAAX cysteine were then converted into electrophilic lead compounds for cellular and in vivo studies. Specific lead compounds have demonstrated Ras-dependent growth arrest cells and are being further developed by the Renslo Lab in collaboration with TheRas, Inc. (K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions, Ostrem, et al, Nature, 2013, 503, 548-51)