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
13/06/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
13/06/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
12/06/2026
YES Network and The Gotham Sports App will air seven Athletes Unlimited Softball...
12/06/2026
The United Football League will host its FAST Innovation Suite at the 2026 United Bowl presented by Credit One Bank on Saturday, June 13 at 3:00 p.m. ET at Audi...
12/06/2026
PTZOptics and LayerJot will present live demonstrations at InfoComm 2026 showing how natural-language AI prompting, robotic camera control, and on-device comput...
12/06/2026
MultiDyne Video and Fiber Optic Systems will exhibit at InfoComm 2026, featuring...
12/06/2026
Ateme has announced that Eurovision Services is using Ateme's software-based frame-rate conversion technology for international live event workflows. The de...
12/06/2026
Bitmovin and Simplestream have announced a partnership with Xperi to simplify the launch of OTT streaming services on TiVo OS smart TVs and devices. The collabo...
12/06/2026
Net Insight has announced that a multinational technology company is deploying a...
12/06/2026
MLB Players Inc., the business arm of the MLB Players Association, has announced a partnership with Athletes First to develop and sell brand partnerships across...
12/06/2026
Guntermann and Drunck (G&D) and VuWall have announced the CommandKeyboard-Advanc...
12/06/2026
Comcast Smart Solutions announces a new smart technology deployment with Major L...
12/06/2026
Elevation Worship completed the initial leg of its Elevation Nights 2026 tour ...
12/06/2026
AJA Video Systems has announced KONA IP25 support for Colorfront Transkoder and ...
12/06/2026
Audinate Group Limited (ASX: AD8) will exhibit at InfoComm 2026 (Booth C7321, Ce...
12/06/2026
Pac-12 Commissioner Teresa Gould has announced the appointment of Scott Adametz as Chief Technology Officer. The Pac-12 describes the hire as the first CTO appo...
12/06/2026
Grass Valley has announced AMPP Edge Live, a production system combining Grass Valley hardware, NVIDIA Blackwell GPU acceleration, and AMPP OS in a single platf...
12/06/2026
At one time a trailblazer with the launch of the Longhorn Network, the Universit...
12/06/2026
Ratings Roundup is a rundown of recent rating news and is derived from press rel...
12/06/2026
Chyron has announced PAINT 10.4, an update to its illustrated replay and sports ...
12/06/2026
SVP, Production Mark Gross: With the new schedule, with not having every Sunday night, it's given us an opportunity to take a step back and reimagine what ...
12/06/2026
For Televisa Technical Engineering Manager Roberto N nez Ibarra and the small team of 12 technicians and two production personnel at the IBC things are already ...
12/06/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
12/06/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
12/06/2026
AJA Announces KONA IP25 Integration with Colorfront Software
Brie Clayton June 12, 2026
0 Comments
Collaboration enables uncompressed SMPTE ST 2110 I/O ...
12/06/2026
URSA Cine 12K LF Used to Create Visuals for STUTS' K-Arena Concert
Brie Clayton June 12, 2026
0 Comments
Organic visuals projected on a giant scre...
12/06/2026
MTI FILM Acquires Mango New Edit, Expanding its Global Post-Production Services ...
12/06/2026
AI Point Tracking Speeds Up Complex VFX Tracks in Mocha Pro
Jessie Electa Petrov June 12, 2026
0 Comments
The 2026.5 release adds automatic point trac...
12/06/2026
Bitmovin, a provider of video streaming solutions, has partnered with Simplestream, a provider of OTT and broadcast solutions, and technology provider Xperi, to...
12/06/2026
Leostream Corporation, creator of the world-leading Leostream Remote Desktop Access Platform, today announced Jigsaw24, a leading B2B IT solutions provider wit...
12/06/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
12/06/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
12/06/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
12/06/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
12/06/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
12/06/2026
AgentPerf from Artificial Analysis, the industry's first agentic AI benchmark, gives developers, enterprises and infrastructure providers a clear way to com...
12/06/2026
Back to All News
Netflix Unveils First-Look Images from Villaflor, Santiago Mitre's New Film
Entertainment
12 June 2026
GlobalArgentina
Link copied to ...
12/06/2026
Back to All News
Cross the Boundaries of the Real World into the Spirit Realm i...
12/06/2026
A fentanyl countermeasure that adapts to combat future black-market drugs Scripps Research scientists developed a vaccine that teaches the immune system to rapi...
11/06/2026
The immense size of the tourney and its Atlantic-spanning operation also disting...
11/06/2026
Nielsen has released a new soccer fandom consumer research report, The Fans Behind The Game: FIFA World Cup 2026 Edition, examining the soccer audience in the...
11/06/2026
Telemundo will launch its FIFA World Cup 2026 coverage on Thursday, June 11 with...
11/06/2026
FuboTV Inc. has announced a distribution agreement with NBCUniversal. Fubo customers can now stream Telemundo and Universo, with NBC Sports Network (NBCSN), NBC...
11/06/2026
DAZN has announced its in-app features for FIFA World Cup 2026 coverage in Spain...
11/06/2026
Roblox has released the 2026 Roblox Digital Expression Report: Wave 4 - Sports D...
11/06/2026
FIFA has unveiled DNA, the Official FIFA World Cup 2026 Anthem, performed by A...
11/06/2026
ESPN will provide English- and Spanish-language news and information coverage of FIFA World Cup 2026 across its U.S. media platforms from June 11 through July 1...
11/06/2026
The latest product of the outstanding RIT Sports Network program, this recent grad from Long Island is carving out a promising path in broadcast engineering
In...
11/06/2026
DAZN has announced a multi-year agreement to make DSPORTS channels available to ...
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.
