A New Approach to Cancer Drug Discovery
September 29, 2017
Scientists at The Scripps Research Institute (TSRI) have developed and demonstrated a promising new strategy for the discovery of novel anti-cancer therapies.
The TSRI scientists, collaborating with scientists at Pfizer, used their new approach to find small-molecule inhibitors of a protein that is important for the growth of non-small-cell lung cancers (NSCLCs). These cancers represent about 85 percent of lung cancers and are relatively insensitive to drug treatment.
This new approach shows promise for identifying previously unrecognized druggable' targets in cancers that lack effective treatments, said senior investigator Benjamin F. Cravatt, Professor and Co-chair of the Department of Molecular Medicine at TSRI.
The new approach, described this week in Cell, is based on a set of sophisticated proteomics methods developed by Cravatt and colleagues in recent years. At the core of these methods is the recognition that certain amino acids on proteins have a special chemical reactivity that allows them to form irreversible covalent bonds with suitably designed probe or scout molecules. Scientists can apply such molecules to a large collection of proteins, even the entire protein contents of a cluster of cells, to quickly identify proteins that have these reactive amino-acids which would be considered potential drug targets.
For the study, Cravatt and colleagues, including co-first authors Liron Bar-Peled, a postdoctoral research associate, and Esther K. Kemper, a graduate student, sought to apply this proteomics strategy to the discovery of potential drug targets in NSCLCs that are supported by over-activity of the transcription factor NRF2.
NRF2 acts as an on-switch for a powerful antioxidant response. Some cancer cells use this response forcing it to stay active always to protect themselves from the cell-damaging oxidative byproducts of their unusual metabolic activity and runaway growth.
Pharmaceutical companies haven't yet developed a drug that can switch off NRF2 in the substantial portion of NSCLCs that depend on its over-activity. Part of the reason is that NRF2 regulates the activities of genes expressed in cell types throughout the body, so a powerful NRF2-blocking agent could have excessive side effects. The researchers therefore looked for downstream elements in the NRF2 pathway that might be more easily and safely targetable.
To start, they used their proteomics platform, including a probe molecule, to identify reactive cysteine amino-acids within proteins in NRF2-driven NSCLC cells. Knocking down the expression of NRF2 in the cells, they observed how the reactivity of those cysteines changed.
Most of these NRF2-related changes in reactivity, as expected, came from changes in the production of these proteins with NRF2's absence. But about 20 percent of these reactivity changes appeared to be due chiefly to oxidative modifications to the proteins as a result of the buildup of reactive oxygen molecules in the cells.
Usually you think of a transcription factor such as NRF2 as regulating an enzyme's function simply by changing the level of that enzyme, said Bar-Peled. In these cases, it appears that NRF2 is shaping the enzymes' environment to be more conducive to their proper function.
The team next used a pair of more selective cysteine-binding probes in NSCLC cells to identify potentially drug-targetable cysteines that met two criteria: first, their reactivity changed greatly with NRF2's activity, and second, their host proteins were primarily restricted in expression to NSCLCs driven by overactive NRF2.
One of the most promising targets meeting these criteria was in a protein called NR0B1. The scientists found that NR0B1 normally works in the nucleus in lung cancer cells as part of a larger protein complex to regulate gene expression. Screening a small-molecule compound library, they found two compounds that attach covalently to a reactive cysteine in NR0B1, resulting in disruption of its protein complexes.
The scientists used the compounds as probes for studying NR0B1's functions, and confirmed that the protein contributes to NRF2's program of gene activity. They also used the compounds to provide evidence that targeting NR0B1 could be therapeutic.
We were able to block and disrupt NR0B1's functional output in these NRF2-activated lung cancers so that the cancers' abnormal growth was reduced, Bar-Peled said. More generally, our findings demonstrate the existence of novel druggable proteins in cancer cells. NR0B1 was not previously known to have an ability to bind small molecules and would have therefore been considered difficult to hit with drugs.
The researchers are now following up by investigating other potentially druggable proteins uncovered in the study. But they see the research above all as an initial demonstration of the power of their new approach to uncover new biology and new drug targets in hard-to-treat cancers.
Other co-authors of the paper, Mapping Druggable Vulnerabilities in a Genetically Defined Cancer, were Radu M. Suciu, Ekaterina V. Vinogradova, Keriann M. Backus, Benjamin D. Horning, Bernard P. Kok, Melissa M. Dix, and Enrique Saez, of TSRI; Robert U. Svensson and Reuben J. Shaw of the Salk Institute for Biological Studies; Max W. Chang of UC-San Diego; and Thomas A. Paul, Zhou Zhu, Nathan Ihle, Ping Jiang, and Matthew M. Hayward of Pfizer.
Support was provided by the National Institutes of Health (CA087660, CA132630, CA172229, CA215249-01, CA211526, CCSG P30 014195), the Chapman Foundation, the Helmsley Charitable Trust, the Damon Runyon Cancer Research Foundation, the American Cancer Society, and the Life Sciences Research Foundation.
Cancer Chemistry Cravatt, Benjamin Partnerships
Most recent headlines
09/11/2025
Dalet today announced a transformative leap forward for media operations: Agentic Artificial Intelligence (AI) that unifies the Dalet ecosystem under one natura...
23/10/2025
A deadline is looming for a new carriage deal between Verizon's Fios TV and Nexstar, with both Verizon and the pay TV-backed American Television Alliance bl...
23/10/2025
NEW YORK During a high-profile session at NAB Show New York, new survey data was shared that revealed significant public concern over artificial intelligence (A...
23/10/2025
BELLEVUE, Wash. and NEW YORK Fox Weather has tapped T-Mobile has as its preferred communications provider and announced that all Fox Weather reporters are being...
23/10/2025
PBS and Amazon Web Services have announced the network is using generative AI to provide enhanced search results to viewers on the PBS App and PBS LearningMedia...
22/10/2025
Prime Video Inks Deal To Present NFL Black Friday Game Worldwide By SVG Staff
Wednesday, October 22, 2025 - 10:06 am
Print This Story | Subscribe
Story ...
22/10/2025
NBA Tip-Off: ESPN Goes 1080p HDR End-to-End, Flipping HDR Switch on REMI and REM...
22/10/2025
FloSports Empowers Division II, III Athletic Departments With Turnkey Production...
22/10/2025
Wall Street Video Summit Debuts, Bringing Together 200 Financial Enterprise Vide...
22/10/2025
Dueling Pianos: International Chopin Piano Competition Is as Competitive as a Ba...
22/10/2025
In 1995, a young Colombian artist released an album that would change Latin pop ...
22/10/2025
Over the past few months, a photovoltaic system has been installed on a three-he...
22/10/2025
The Orion spacecraft for NASA's Artemis II mission is stacked on the Space Launch System (SLS) rocket in High Bay 3 of the Vehicle Assembly Building at Kenn...
22/10/2025
L3Harris' Hybrid SATCOM is resilient by design, offering path diversity that eliminates vulnerabilities by routing data across the best available networks i...
22/10/2025
WASHINGTON, D.C. Organizers of NAB Show New York said they are expecting more than 12,000 registered attendees from about 100 countries along with 260 exhibitor...
22/10/2025
WASHINGTON, D.C The organizers of The 2025 NAB Show New York have announced that they are expecting more than 12,000 registered attendees from about 100 countr...
22/10/2025
Masque Sound, a leading theatrical sound reinforcement, installation and design company, supplied an extensive gear package of professional-grade equipment for ...
22/10/2025
Lightware, a global leader in signal management and AV connectivity solutions, is seeing strong market momentum for the UCX-3x3-TPX-RX20, a compact transmitter-...
22/10/2025
MELVILLE, N.Y. Chyron has released PAINT 10.2, the latest update for its telestration platform, adding support for SMPTE ST 2110 IP workflows, expanding brandin...
22/10/2025
WASHINGTON Run3TV today said NBCUniversal is joining as an investor in the ATSC 3.0 Framework Authority, which develops the Run3TV NextGen TV application platfo...
22/10/2025
ATLANTA swXtch.io will feature two new networking solutions extending the company's reach across more cloud and on-prem workflows at NAB Show New York, set ...
22/10/2025
The Warner Bros. Discoverys HBO Max streaming services has increased prices for all its streaming tiers effectively immediately for new customers. Existing cust...
22/10/2025
LOS ANGELES OpenDrives has signed a new distribution partnership deal with Versatile Distribution Services (VDS) to strengthen its channel and streamline how it...
22/10/2025
WASHINGTON, D.C The organizers of The 2025 NAB Show New York have announced that they are expecting more than 12,000 registered attendees from about 100 countr...
22/10/2025
Samora Pinderhughes Brings Immersive Sound to Berklee's Signature Series The artist and composer, who's worked with Herbie Hancock, Robert Glasper, Co...
22/10/2025
BMI Day at Berklee Celebrates Composer Fil Eisler and Awards Scholarship to Stud...
22/10/2025
October 22nd, 2025 TRIBECA ANNOUNCES STAR-STUDDED LINEUP OF MEMBERSHIP EVENTS F...
22/10/2025
Rohde & Schwarz and TRUMPF cooperate in drone defense Rohde & Schwarz and TRUMPF partner to deliver a comprehensive drone defense solution combining Rohde & S...
22/10/2025
European Broadcaster Upgrades To Grass Valley's NativeIP LDX 135 Cameras And...
22/10/2025
Everyone Gets a Better Deal on Verizon with New FOX One Perk The $15 FOX One streaming service perk is yet another way Verizon continues to add savings for cu...
22/10/2025
First Look Hidden Assets Series 3
Premieres on 9th November 9:30pm on RT One & RT Player
WATCH HERE Promo Link: Hidden Assets Series 3 | RT
The Crimin...
21/10/2025
NAB New York 2025: Although AES Show Is on Its Own, Audio Will Be a Major Part o...
21/10/2025
NAB New York 2025: Business of Broadcast and Media,' Future of Content'...
21/10/2025
SVG All-Stars: Ethan Folz, Senior Director, Digital Operations and Quality of Ex...
21/10/2025
NBA on NBC/Peacock: Livestream Offers Graphic Overlays, Predictive Gaming, Ancil...
21/10/2025
NBA on NBC/Peacock: At the Front Bench With Producer Frank DiGraci and Director ...
21/10/2025
NBA on NBC/Peacock: NBC Sports, NEP Build Ultra-Flexible Production Plan That Se...
21/10/2025
Indigenous storytelling has been at the heart of the work of the Sundance Instit...
21/10/2025
Top L-R: Mysterious Skin, American Dream Second Row L-R: Little Miss Sunshine, D...
21/10/2025
Last week, Spotify and Columbia Records transformed Pier 4 at the Brooklyn Army ...
21/10/2025
SBS Learn's Dharug Ngurra resource empowers classrooms to meaningfully celeb...
21/10/2025
As global operators simplify and evolve their digital platforms, NPS improvement...
21/10/2025
Critical Design Review completion is a key milestone on the path toward Wideband Global Satellite Communications certification for the network in 2026, opening ...
21/10/2025
New Australian undersea training range to implement and improve warfighting tactics, proficiency and safety; enable joint/allied training that contributes to pr...
21/10/2025
eds3_5_jq(document).ready(function($) { $(#eds_sliderM519).chameleonSlider_2_1({...
21/10/2025
September, the beginning of autumn, brought an expected revival to the TV market, largely due to the new fall TV schedules. The time spent in front of the TV sc...
21/10/2025
Broadcast Booms with 20% Uptick vs. August, Achieving Largest Monthly
Increase ...
21/10/2025
During September, streaming's share of TV viewing in Mexico settled at 24.5%, a marginal shift of -0.5 share points from the previous month.
Disclaimer: YU...
21/10/2025
RENNES, France BBright and GlobalM have conducted a technical trial validating Ultra HD interoperability across the entire contribution chain in the cloud, achi...
A New Approach to Cancer Drug Discovery 
