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
26/03/2026
Extron and Audio-Technica have announced that their Design Solutions devices, Ce...
26/03/2026
SPORTEL Asia took place March 24-25 at the Orchard Hotel Singapore, drawing 370 participants representing more than 220 companies from 35 countries. Approximate...
26/03/2026
LTN will demonstrate satellite-to-IP migration solutions for broadcasters, cable networks, MVPDs, and station groups at NAB Show 2026 (Booth W2100).
The C-Ban...
26/03/2026
The Seattle Mariners have partnered with Daktronics to install an upgraded outfi...
26/03/2026
The Esports Foundation (EF) has awarded National Team Partner status to organizations and individuals across more than 100 countries and territories for the Esp...
26/03/2026
Telestream has announced expanded integration between its Vantage workflow platf...
26/03/2026
FOR-A Corporation has announced a partnership with Nippon TV and NVIDIA to distr...
26/03/2026
CBS Sports and the WNBA have expanded their partnership through a new long-term, multiplatform rights agreement. CBS Sports will feature up to 20 regular-season...
26/03/2026
Zac Brown Band will star in the Sunday Night Baseball show open on NBC and Peacock, NBC Sports announced. The open was filmed at American Family Field, home of ...
26/03/2026
Major League Baseball opens the 2026 season with nationally televised games across multiple media partners. Fans can visit MLB.com/Watch for a complete schedule...
26/03/2026
DIRECTV has announced an agreement to carry nine new MLB-operated team channels, covering the Cincinnati Reds, Detroit Tigers (Detroit SportsNet), Kansas City R...
26/03/2026
Nationals.TV, the Washington Nationals' local broadcast channel, is now avai...
26/03/2026
Starting Thursday, March 26, MLB.TV will be available on the ESPN App, giving fans access to more than 2,000 out-of-market regular season games. Fans can also r...
26/03/2026
By Matt Klein
Hello to everyone reading this - whether you're a current YEP, HPA member, or just YEP-curious. I'm Matt Klein, one of the co-chairs of t...
26/03/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
26/03/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
26/03/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
26/03/2026
28 participating companies, from start-ups to blue-chips, lead the UK Group as part of the GREAT Britain and Northern Ireland presence across all the Halls at N...
26/03/2026
Arkona Unveils BLADE//planner and Major Usability Enhancements at NAB 2026
Brie Clayton March 26, 2026
0 Comments
New graphical configuration tool and...
26/03/2026
Bitfocus showcases complete control at NAB Show 2026
Brie Clayton March 26, 2026
0 Comments
Continuing development drives advances in security, availa...
26/03/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
26/03/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
26/03/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
26/03/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
26/03/2026
Nevion introduces powerful new Panel Builder to enhance VideoIPath broadcast con...
26/03/2026
2026 Oscar Nominated Films Powered by Blackmagic Design
Brie Clayton March 25, 2026
0 Comments
DaVinci Resolve Studio used on 27 of this year's no...
26/03/2026
Leader to present full suite of advanced Test & Measurement solutions at NAB Sho...
26/03/2026
Boston Conservatory to Present New England and Collegiate Premiere of Groundbrea...
26/03/2026
Back to All News
Have a Wish Worth Dying For? Netflix's First Korean YA Hor...
26/03/2026
Back to All News
The Truthers, Starring Jose Coronado and St phanie Magnin, Pre...
26/03/2026
Editor's note: This post is part of Into the Omniverse, a series focused on ...
26/03/2026
That gaming backlog won't clear itself - GeForce NOW is here to help. Stream the latest titles straight from the cloud across a variety of devices.
This we...
25/03/2026
Live match directors Sarah Cheadle (Sky Sports), Rob Levi (TNT Sports), and Andrew Swift (BBC Sport) sit down with the Premier League's Rachel Nightingale t...
25/03/2026
The senior from Upstate New York is manning the mic while also interning for the athletic department's sports-information team
In the live-sports-video ind...
25/03/2026
Synamedia has announced ContentArmor Edge Watermarking, a server-side solution t...
25/03/2026
SES has announced meoSphere, a medium Earth orbit (MEO) satellite network targeted for operation by 2030. The first phase will pair SES-developed software-defin...
25/03/2026
TVU Networks is working with Reuters on a phased migration from satellite to a c...
25/03/2026
Nielsen has announced three senior appointments. Seth Ladetsky has been named Head of Global Sports. Trevor Fellows will lead Nielsen's advertiser and agenc...
25/03/2026
Anoki and Amagi have launched In-Scene Ads powered by Anoki ContextIQ across Amagi's portfolio of in-content ad formats for Free Ad-supported Streaming TV (...
25/03/2026
Arkona Technologies will announce a series of enhancements to its BLADE//runner platform at NAB 2026 (Booth C.1808). The updates focus on usability and workflow...
25/03/2026
Daktronics has installed two tower displays and a video wall in the Lexus Club at Petco Park in San Diego ahead of the 2026 season.
Continuing to improve the ...
25/03/2026
MultiDyne Video & Fiber Optic Systems is celebrating its 50th anniversary as NAB Show 2026 approaches. The company was founded in 1976 by Vincent Jachetta, an N...
25/03/2026
IPC, a provider of integrated communication solutions, will make its NAB 2026 de...
25/03/2026
Live production categories were led by NBC, FOX, and ESPN's NFL coverage...
25/03/2026
The Atlanta Braves and Spectrum have announced a multiyear distribution agreemen...
25/03/2026
(L-R) Charlie Tyrell and Daniel Roher attend The AI Doc: Or How I Became An Apocaloptimist Premiere during the 2026 Sundance Film Festival at The Ray Theatre ...
25/03/2026
L3Harris Technologies and RFTEQ Pty Ltd signed a memorandum of understanding to ...
25/03/2026
L3Harris delivers combat-ready Torpedo Tube Launch and Recovery system, which deploys and retrieves Iver4 900 autonomous underwater vehicles through submarine t...
25/03/2026
The company expands leadership team under Chief Revenue Officer Amilcar Perez
S...
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.
