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
17/12/2025
Investigative journalists across the Western Balkans and T rkiye continue to con...
17/12/2025
Sports Broadcasting Hall of Fame Inducts 10 Industry Icons During Unforgettable ...
17/12/2025
ESPN to Debut MNF Playbook with Next Gen Stats, a New AI-Driven NFL Data-AltCastThe series, powered by Adrenaline TruPlay AI, launches Dec. 22 and runs through ...
17/12/2025
Inaugural Optum Golf Channel Games Debut Under the Lights' in Primetime on ...
17/12/2025
The right playlist is essential on New Year's Eve, building the energy as you get ready and keeping it high as you count down to midnight. This year, Spotif...
17/12/2025
eds3_5_jq(document).ready(function($) { $(#eds_sliderM519).chameleonSlider_2_1({...
17/12/2025
Audiences Watched Over 103 Billion Minutes of TV on Thanksgiving Day
NFL Games ...
17/12/2025
Share Share by:
Copy link
Facebook
X
Whatsapp
Pinterest
Flipboard...
17/12/2025
Share Share by:
Copy link
Facebook
X
Whatsapp
Pinterest
Flipboard...
17/12/2025
Share Share by:
Copy link
Facebook
X
Whatsapp
Pinterest
Flipboard...
17/12/2025
Share Share by:
Copy link
Facebook
X
Whatsapp
Pinterest
Flipboard...
17/12/2025
Share Share by:
Copy link
Facebook
X
Whatsapp
Pinterest
Flipboard...
17/12/2025
Share Share by:
Copy link
Facebook
X
Whatsapp
Pinterest
Flipboard...
17/12/2025
Share Share by:
Copy link
Facebook
X
Whatsapp
Pinterest
Flipboard...
17/12/2025
Share Share by:
Copy link
Facebook
X
Whatsapp
Pinterest
Flipboard...
17/12/2025
Share Share by:
Copy link
Facebook
X
Whatsapp
Pinterest
Flipboard...
17/12/2025
Share Share by:
Copy link
Facebook
X
Whatsapp
Pinterest
Flipboard...
17/12/2025
Share Share by:
Copy link
Facebook
X
Whatsapp
Pinterest
Flipboard...
17/12/2025
KPop Demon Hunters Stars Visit Berklee for Weeklong Celebration Andrew Choi and EJAE, who voiced the film's main characters and contributed to its soundtr...
17/12/2025
Wednesday 17 December 2025
Heated Rivalry will be coming to Sky and streaming service NOW on 10 JanuaryTurn on cookies to view this content. Go to Privacy opti...
17/12/2025
Back to All News
Inside The Unseen World Of Indian Customs: Netflix Reveals The...
17/12/2025
Back to All News
Netflix announces PAPARAZZI KING: the docu series coming to Ne...
17/12/2025
Back to All News
Netflix Unveils First Look at Jo Nesbo's Detective Hole Pr...
17/12/2025
Back to All News
Netflix Welcomes Warner Bros. Discovery Board Recommendation
Business
17 December 2025
Global
Link copied to clipboard
After Careful Revi...
17/12/2025
RT has announced that Kathy Fox has been appointed Commissioning Editor with re...
17/12/2025
The Hao AI Lab research team at the University of California San Diego - at the forefront of pioneering AI model innovation - recently received an NVIDIA DGX B...
17/12/2025
Editor's note: This post is part of Into the Omniverse, a series focused on ...
17/12/2025
With the new season of Dancing with the Stars shimmering in the not-too-distant future this New Year, the celebrity and dancer pairings of the twelve couples ha...
16/12/2025
Hawkins has landed on Spotify, just in time for Stranger Things Season 5, Volume...
16/12/2025
Wherever you are, your favorite music and audio content should go seamlessly with you. That's why Spotify has partnered with NAVER Corp, Korea's leading...
16/12/2025
2025 Wrapped arrived bigger and bolder than ever. This year's experience is designed to be ultra personal and shareable, with new features like Wrapped Part...
16/12/2025
Three 12-kilowatt Advanced Electric Propulsion System thrusters, supplied by L3Harris Technologies, form the core of Gateway's propulsion system. Pictured i...
16/12/2025
The challenge facing America's defense industrial base is not just about speed - its about rebuilding the foundation that makes speed possible. Our nations ...
16/12/2025
Share Share by:
Copy link
Facebook
X
Whatsapp
Pinterest
Flipboard...
16/12/2025
SEVILLE, Spain Canal Sur, the public broadcasting service for Andalusia, Spain, has completed a total technology refresh based on Pebble's resilient, softwa...
16/12/2025
NEW YORK Teleprompting hardware provider Telescript International has acquired all software code and intellectual property previously owned by Telescript West. ...
16/12/2025
As cable operators face increased competition from 5G fixed wireless access providers, a new report from Ookla Research finds that T-Mobile is the FWA speed lea...
16/12/2025
Apple has announced a major upgrade to the Apple TV app for device owners outside the Apple ecosystem with news that the Apple TV app for Android now supports G...
16/12/2025
Space42 grows Direct-to-Device partner ecosystem through a Memorandum of Underst...
16/12/2025
16 Dec 2025
VEON Announces Release Date for Full Year and Fourth Quarter 2025 R...
16/12/2025
16 Dec 2025
VEON's Kyivstar Invests in Renewable Energy in Ukraine with Acq...
16/12/2025
Back to All News
Emma Appleton, Fares Fares, Frida Gustavsson and Jakob Oftebro...
16/12/2025
Back to All News
Docu-reality My Korean Boyfriend Gets a Trailer and Premiere D...
16/12/2025
Harmonic's XOS Advanced Media Processor Improves Streaming Video Quality and Boosts Viewer Engagement SAN JOSE, Calif. - Dec. 16, 2025 - Harmonic (NASDAQ: ...
16/12/2025
RT Sport Awards 2025 live on RT One and RT Player at 8:05pm on Saturday 20 December.
On Saturday 20 December live on RT One and RT Player at the earlier t...
16/12/2025
Singer -songwriter Brian Kennedy has been announced as the final celebrity dance...
15/12/2025
Harlem Globetrotters Celebrate 100th Anniversary With New Brand Campaign From Th...
15/12/2025
Top L-R: La Tierra Del Valor (The Home of the Brave), Mangittatuarjuk (The Gnawe...
15/12/2025
L3Harris will leverage 15 years of experience supporting the E-4B Nightwatch 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.
