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
Most recent headlines
05/01/2027
Worlds first 802.15.4ab-UWB chip verified by Calterah and Rohde & Schwarz to be ...
01/06/2026
January 6 2026, 05:30 (PST) Dolby Sets the New Standard for Premium Entertainment at CES 2026
Throughout the week, Dolby brings to life the latest innovatio...
02/05/2026
Dalet, a leading technology and service provider for media-rich organizations, t...
01/05/2026
January 5 2026, 18:30 (PST) NBCUniversal's Peacock to Be First Streamer to ...
01/04/2026
January 4 2026, 18:00 (PST) DOLBY AND DOUYIN EMPOWER THE NEXT GENERATON OF CREATORS WITH DOLBY VISION
Douyin Users Can Now Create And Share Videos With Stun...
02/03/2026
NBC Sports selected Imaginary Forces to create the main title sequence for the M...
02/03/2026
The NFL announces the launch of the NFL Draft Innovation Challenge, a new crowds...
02/03/2026
The World Teleport Association (WTA) has named Skyline Communications' DataMiner SatOps solution as a finalist for the 2026 Teleport Technology of the Year ...
02/03/2026
Ventum Tech announces a strategic partnership with Pixotope, a real-time graphic...
02/03/2026
Victory , a free, ad-supported sports streaming service, announces the launch of...
02/03/2026
Global powerhouse Delta Goodrem to represent Australia at this year's Eurovi...
02/03/2026
SBS brings together prominent voices to discuss rising social division and seek ...
02/03/2026
NITV Unveils Wednesday Night Sport Night
Media releases
A Midweek Hub for Blak Sport
Flagship NRL program Over The Black Dot moves to Wednesdays at 9:30pm
...
02/03/2026
Rohde & Schwarz demonstrates FR1-FR3 carrier aggregation, advancing 6G readiness Rohde & Schwarz and Qualcomm Technologies, Inc. have reached another pivotal ...
02/03/2026
MELBOURNE, Fla., March 2, 2026 - L3Harris Technologies (NYSE: LHX) today announc...
02/03/2026
Harvey Norman tops New Zealand's biggest ad spenders as retail leads and telcos and beverages sure Auckland March 3, 2026 - Nielsen's New Zealand'...
02/03/2026
aconnic AG (ISIN: DE000A0LBKW6), Munich, and Arqit Quantum Inc. (Nasdaq: ARQQ, A...
02/03/2026
Advanced Systems Group, LLC (ASG), a technology and services provider for media creatives and content owners, has appointed Jody Boatwright as Chief Strategy Of...
02/03/2026
Lightware, an industry leader in signal management, is reinforcing its commitment to simplifying complex AV environments with the continued evolution of its TPN...
02/03/2026
ZEISS Cinema opens its doors to an exclusive screening, filmmakers Q&A and hands-on showcase of the new ZEISS Aatma lens family on Tuesday, March 10, 6:00-9:00 ...
02/03/2026
To expand the creative potential of the compact Astera QuikBeam, DoPchoice introduces the SNAPBAG Round. The new light-shaping accessory transforms the powerfu...
02/03/2026
Douglas Dubler
On a rooftop in New York City, veteran photographer Douglas Dubler watched the sun's angle shift across the urban landscape, his internal cl...
02/03/2026
ZEISS is expanding its Otus ML lens family with the introduction of the new ZEISS Otus ML 1.4/35. This manual-focus lens is designed for photographers who live ...
02/03/2026
Matthews Studio Equipment now offers the new Dinkum Systems White FlexiMount and Phone Mount Kit, a compact, highly adaptable setup for mobile content creation...
02/03/2026
Luxembourg, February 26, 2026 - SES and Africa Mobile Network (AMN) have expande...
02/03/2026
02 03 2026 - Media release Ausfilm and Screen Australia launch joint UK market initiative
Ausfilm and Screen Australia have announced Partner with Australia (...
02/03/2026
Monday 2 March 2026
Saturday Night Live UK announces writing team
L-R: Jonno Johnson; Charlie Skelton; Celya AB; Omar Badawy; Gr inne Maguire; Laura Claxton; ...
02/03/2026
Back to All News
Netflix Unveils the Trailer for 53 Sundays, the New Film by Cesc Gay
Entertainment
02 March 2026
GlobalSpain
Link copied to clipboard
Dis...
28/02/2026
With two features seen in Formula 1 coverage, the broadcaster aims to bring view...
28/02/2026
Secretary of War Pete Hegseth addresses a crowd of approximately 1,500 L3Harris employees in Camden, Arkansas, as part of his Arsenal of Freedom tour....
28/02/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
28/02/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
28/02/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
28/02/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
28/02/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
28/02/2026
Berklee Presents Mambo Mania: Eguie Castrillo and the Berklee All-Stars Big Band...
28/02/2026
Berklee Announces Two New Summer Programs in Los Angeles The Berklee Music Business Program and Electronic Music Production and Sound Design Workshop bring imme...
28/02/2026
AI-RAN is moving from lab to field, showing that a software-defined approach is ...
28/02/2026
Autonomous networks - intelligent, self-managing telecommunications operations -...
28/02/2026
Back to All News
Final Trailer for BEASTARS Final Season Part 2' Roars Tow...
28/02/2026
New way to intentionally discover molecular glues could expand drug discovery Scripps Research scientists and colleagues show how drugs that eliminate certain d...
27/02/2026
The E.W. Scripps Company names Oliver Gray as Vice President, Network Sports and...
27/02/2026
The Gotham Sports App, the exclusive direct-to-consumer streaming home of MSG Networks and the YES Network, is now available for purchase through Prime Video fo...
27/02/2026
ESPN and the Horizon League announce a new multi-year, multi-platform media rights agreement, continuing a 38-year collaboration that began with the 1988 Midwes...
27/02/2026
At the 2026 NAB Show in Las Vegas, NETGEAR will highlight its new switch models and major updates to its Engage Controller software. The company's network d...
27/02/2026
Riedel Communications announces that Fondazione Teatro alla Scala has deployed a...
27/02/2026
Lyuno specializes in media localization, including translation, dubbing, subtitling, and voice-over services for a wide array of entertainment content. The comp...
27/02/2026
Chyron Weather 2.3, the latest edition of Chyron's weather visualization suite for broadcasters and meteorologists, recently launched.
The release includes...
27/02/2026
Telestream, which concentrates in media workflow technologies, announces expanded practical AI enhancements across its Vantage, Vantage Cloud, EDC, Stanza, and ...
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.
