
Seeing double: Designing drugs that target twin cancer proteins Scripps Research scientists used knowledge about a protein to characterize drugs that selectively bind to its twin, or paralog.
September 30, 2024
LA JOLLA, CA Some proteins in the human body are easy to block with a drug; they have an obvious spot in their structure where a drug can fit, like a key in a lock. But other proteins are more difficult to target, with no clear drug-binding sites.
To design a drug that blocks a cancer-related protein, Scripps Research scientists took a hint from the protein's paralog, or twin. Using innovative chemical biology methods, the scientists pinpointed a druggable site on the paralog, and then used that knowledge to characterize drugs that bound to a similar but more difficult to detect spot on its twin. Ultimately, they found drugs that only bound to the protein of interest and not its highly similar sibling.
Their approach, described in Nature Chemical Biology on September 18, 2024, and dubbed paralog hopping, could uncover new binding sites for drugs and inform drug development more broadly, since nearly half of the proteins in human cells including many involved in cancer and autoimmune diseases have such paralogs.
This method may be generally useful in cases where you have paralogs, and you are trying to find a new drug for one of them, says senior author Benjamin Cravatt, PhD, the Norton B. Gilula Chair in Biology and Chemistry at Scripps Research. Being able to target one paralog over another is an important goal in drug development, as two paralogs often have different functions.
Many genes have duplicated throughout evolution, resulting in multiple copies in the human genome. In some cases, copies have evolved slightly different sequences from each other, making their corresponding proteins into paralogs. These protein paralogs remain highly similar in structure and often have redundant or overlapping functions within cells.
In recent years, Cravatt's research team formulated an approach to develop drugs that bind to the amino acid cysteine a protein building block with unique, highly reactive chemical properties. The scientists' method takes advantage of cysteines as an optimal site for drugs to attach to a protein permanently, often inactivating it. However, not all proteins have accessible cysteines. In the cases of paralog pairs, one protein may have a druggable cysteine that the other does not.
We started with this idea that if you know how to drug one protein, you can figure out how to drug its paralog in a similar way, says Yuanjin Zhang, a graduate student at Scripps Research and first author of the new paper.
As a test case, the team tackled the paralog pair known as CCNE1 and CCNE2. Both proteins have been found to be overactive in breast, ovarian and lung cancer. However, scientists suspected that the two proteins play slightly different roles. The team posited that turning off just one protein could make treating some cancers more effective.
It has been difficult, however, to design drugs that target the CCNE1 and CCNE2 proteins to test this hypothesis. Cravatt, Zhang and their colleagues knew that CCNE2 had a druggable cysteine, while CCNE1 did not. If they could identify drugs that bound to the same spot on CCNE1, even in the absence of a cysteine, they suspected the protein would shut off.
The scientists first engineered a cysteine into CCNE1, mimicking the drug-binding spot they had pinpointed in CCNE2. They then leveraged this neo-cysteine to identify drugs that bind to CCNE1. Next, they screened a library of other chemical compounds for the ability to compete with that drug in binding to CCNE1. The team reasoned that some of the compounds that competed for the same spot would bind in ways that did not rely on the cysteine.
Indeed, Cravatt, Zhang and their colleagues discovered multiple compounds that could bind to the same site on CCNE1 even when the cysteine was removed again. Some compounds did not bind to CCNE2. Some also had opposite functions, stabilizing the molecule so that it might be more active than usual, rather than inactivating it. Structural studies revealed that the CCNE1 compounds bind to a cryptic pocket that was not previously known to be druggable.
The team says the approach highlights the importance of screening for drugs in diverse, creative ways.
If we had just screened looking for compounds with a particular function, we would not have identified all of these various functional molecules, and if we had just looked at the structure of CCNE1, we would not have found this binding pocket at all, says Zhang.
More research is needed to discover whether the new compounds have potential utility in treating cancer or other diseases in which CCNE1 plays a role. Next, the scientists plan to apply their paralog-hopping method to other pairs of proteins important for tumorigenesis.
In addition to Cravatt and Zhang, authors of the study, An allosteric cyclin E-CDK2 site mapped by paralog hopping with covalent probes, include Zhonglin Liu, Sang Joon Won, Divya Bezwada and Bruno Melillo of Scripps Research; and Marsha Hirschi, Oleg Brodsky, Eric Johnson, Asako Nagata, Matthew D. Petroski, Jaimeen D. Majmudar, Sherry Niessen, Todd VanArsdale, Adam M. Gilbert, Matthew M. Hayward, Al E. Stewart and Andrew R. Nager of Pfizer, Inc.
This work was supported by funding from the National Cancer Institute (R35 CA231991) and Pfizer.
Chemistry Cravatt, Benjamin
North America Stories
21/05/2026
Game Creek Video Columbia and Celtic, NEP Supershooter 8 will house onsite produ...
21/05/2026
Freshly graduated, this upstart producer, director, and camera operator is already working as an AP on videoboard shows for the Philadelphia Phillies
In the li...
21/05/2026
Media Links has announced a channel partnership with Clearcast Asia, a broadcast...
21/05/2026
SiriusXM and NASCAR have announced a multi-year renewal of their broadcasting agreement. SiriusXM will continue to carry live broadcasts of every NASCAR Cup Ser...
21/05/2026
Audio-Technica held a demonstration event at its Technica House location in New ...
21/05/2026
Ateme has announced that RTL Deutschland has selected Ateme's software-based...
21/05/2026
LiveU has announced that BCC Live deployed the LU900Q intelligent production unit for the first time during the 2026 Memorial Hermann IRONMAN Texas North Americ...
21/05/2026
ATSC has announced that Mark Aitken, President of ONE Media and Senior VP of Advanced Technology at Sinclair Broadcast Group, will receive the 2026 Mark Richer ...
21/05/2026
BBright has published a technical analysis of the Media eXchange Layer (MXL), de...
21/05/2026
The Esports Foundation has announced that the 2026 Esports World Cup (EWC) will be hosted in Paris, France, from July 6 through August 23. The event marks the f...
21/05/2026
Chyron has announced PRIME Scorebug, a scorebug solution built on the PRIME Platform for on-premises sports production, and has expanded Chyron LIVE with purpos...
21/05/2026
Media Links has announced the integration of its Xscend IP transport platform with Skyline Communications' DataMiner xOps platform. The integration will be ...
21/05/2026
As live sports productions continue to demand more flexible, scalable, and cost-...
21/05/2026
In advance of this year's Sports Emmy Awards, SVG is taking a deep dive into...
21/05/2026
Hey Miami & Atlanta post-production folks!
Shade is hosting a free private suite at a Braves game (6/2) and Marlins game (6/5) and have about a dozen extra tic...
21/05/2026
The Suns and Mercury become the first NBA and WNBA teams to make games available under a single broadcast partner across both over-the-air and streaming....
21/05/2026
iPhones are part of the the regular production rotation for Friday Night Baseba...
21/05/2026
In advance of this year's Sports Emmy Awards, SVG is taking a deep dive into...
21/05/2026
Heather Matarazzo as Dawn Wiener in Todd Solondz's Welcome to the Dollhouse...
21/05/2026
SKY RAIDER II INTERNATIONAL's modular open systems architecture delivers expanded operational reach and mission flexibility....
21/05/2026
ASO-enabled WESCAM MX-10 systems conduct systematic wide-area maritime search patterns, autonomously managing sensor scan operations to expand coverage, reduce ...
21/05/2026
HBO Max, a new addition to Gracenote Data Hub, is home to the most sports programming among major streamers
NEW YORK May 21, 2026 New analysis by Gracenote...
21/05/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
21/05/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
21/05/2026
The UK's leading event for the creative industries united thousands of professionals for two days of networking, debate, industry insight and getting hands-...
21/05/2026
Recreating Doug Trumbull's Slitscan VFX - After Effects Mastery
Graham Quince May 21, 2026
0 Comments
In this After Effects tutorial, I'm divi...
21/05/2026
Cavalry: An Array of Fun Stuff
Simon Ubsdell May 21, 2026
0 Comments
Arrays are a really powerful feature of Cavalry and here we'll go over some o...
21/05/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
21/05/2026
Bitmovin, a leading provider of video streaming solutions, has announced that streaming service provider, Watch Brasil, has replaced its legacy systems with Bit...
21/05/2026
OWC Launches Dads and Grads Promotion with Exclusive Savings
Brie Clayton May 21, 2026
0 Comments
The gifts they'll actually use - save on cutting...
21/05/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
21/05/2026
For cinematographer Ashley Barron ACS ( Rivals , Dangerous Liaisons , Disney's Doctor Who ), setting the look of Netflix's How to Get to Heaven from ...
21/05/2026
Jean-Fran ois Hensgens, AFC, SBC, (Tueurs, Six Days in Spring, Le Fil) brings his signature visual approach to Cannes 2026 premiering biopic L'Affaire Marie...
21/05/2026
Beeble launches Canvas, a node-based AI compositor for VFX and Virtual Productio...
21/05/2026
Shelly Johnson Elected President of American Society of Cinematographers
Brie Clayton May 20, 2026
0 Comments
The American Society of Cinematographers...
21/05/2026
ARRI expands Management Board to accelerate next phase of growth and innovation
Brie Clayton May 20, 2026
0 Comments
ARRI expands its Management Board...
21/05/2026
Back to All News
In a Broken System, How Far Will You Bend? Netflix Releases Ma...
21/05/2026
Back to All News
RHYTHM FLOW ITALY: The Trailer Is Out Now For the Third Seas...
21/05/2026
Back to All News
Our Latest Steps to Make Content More Accessible
Product
21 May 2026
Global
Link copied to clipboard
Download all assets
Listen to the a...
21/05/2026
The mission begins now.
GeForce NOW is dialing up the action with a blockbuster...
20/05/2026
True to the Music City theme, the Tennessee Titans plan to make live music a prominent fixture on game days at the new venue
Reflecting the continuing converge...
20/05/2026
The long-term goal is innovation for the next generation of hockey rinks at both the professional and the community level
The National Hockey League (NHL) toda...
20/05/2026
End-users and vendors alike work toward cost-effective yet high-quality solution...
20/05/2026
The National Football League has announced that Nashville will host Super Bowl LXIV in 2030 at the new Nissan Stadium. The announcement was made at the NFL Spri...
20/05/2026
The NFL has announced that the 2028 NFL Draft presented by Bud Light will take place in Minnesota, uniting fans from around the world to celebrate one of the mo...
20/05/2026
As professional AV workflows continue to evolve, expectations around audio, video, networking, and control are rising rapidly. At InfoComm 2026 in Las Vegas, La...
20/05/2026
Haivision will showcase its latest innovations at InfoComm 2026, taking place fr...
20/05/2026
A Rotating Detonation Engine being hot fire tested at Purdue University's Zu...
20/05/2026
A U.S. Army VAMPIRE system, assigned to Bravo Battery, 1st Battalion, 51st Air Defense Artillery Regiment, 7th Infantry Division/Multi-Domain Command - Pacific ...
20/05/2026
Cable Captures Only Monthly Increase Among Viewing Categories in March, Earns it...