
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
28/04/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
28/04/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
28/04/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
28/04/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
28/04/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
28/04/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
28/04/2026
Introducing Nx 3-Strip v2 - A Physics-Based Technicolor Reconstruction for DaVin...
27/04/2026
CES Power, a provider of infrastructure for live events, has announced the acquisition of three Ireland-based businesses: GH Energy Rental Ltd, Event Power, and...
27/04/2026
FuboTV Inc. has announced it is developing its Multiview feature for the Fubo streaming service on select LG TVs, including 2024, 2025, and newer 4K and 8K mode...
27/04/2026
Shade, a file management platform for creative teams, has announced a $14 million funding round led by Khosla Ventures, Construct Capital, and Bling Capital, br...
27/04/2026
The Audio Engineering Society (AES) will present the Immersive Audio Academy 12th Edition - Immersive Audio in All Flavors - on April 30, 2026, at 12:00 p.m. ...
27/04/2026
DAZN has announced DAZN48, a creator program for the FIFA World Cup 2026 that will recruit 48 creators - one representing each of the 48 qualified nations - to ...
27/04/2026
FloSports has announced exclusive streaming rights to four CrossFit competitions: Legends Del Mar: CrossFit Semi-Finals, Magic City Games, NorCal Classic, and t...
27/04/2026
Telestream has announced that Pulse, its software-defined test and measurement p...
27/04/2026
Shade has announced it is a Cloud Computing and Storage winner in the 2026 NAB Show Product of the Year Awards. Winners were selected by a panel of industry exp...
27/04/2026
Leading the NBA's video-ads platform, this Penn State grad is at the forefro...
27/04/2026
DAZN has expanded its international broadcast rights for the T100 Triathlon World Tour to include Africa. All races from the T100 calendar will be available for...
27/04/2026
NAB Show has announced the recipients of its 2026 Project of the Year and Product of the Year Awards at a ceremony at the Las Vegas Convention Center.
Each wi...
27/04/2026
DIRECTV has launched on Meta Quest headsets, becoming the first MVPD to offer live TV through the platform. The timing coincides with the stretch run of the MLB...
27/04/2026
TBL Team Boxing League has announced a broadcast agreement with MSG Networks to air all remaining Season 4 fights live across MSG's television and digital p...
27/04/2026
IP integration, interoperability, growth of intercommunications were key concerns for vendors and visitors alike
Attendees at the recently concluded 2026 NAB S...
27/04/2026
Behind The Mic provides a roundup of recent news regarding on-air talent, includ...
27/04/2026
A pro-audio emphasis, spectrum changes, and on-field audio mark the new products and enhancements to existing offerings
Microphones remain the primary point of...
27/04/2026
The Sports Video Group team was all over the NAB Show floor out in Las Vegas las...
27/04/2026
Available for current Nielsen ONE Ads customers, this new capability predicts sa...
27/04/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
27/04/2026
Nippon TV's In-House Proprietary AI Solution AiDi Wins Product of the Year A...
27/04/2026
Outpost Introduces Unlimited Collaboration Model for Review and Approval Workflo...
27/04/2026
Ikegami Announces VFE-P07D Monocular OLED Viewfinder with Tiltable 3.5-inch LCD ...
27/04/2026
Custom Consoles announces the completion of a large Module-R desk and MediaWall monitor display mount for an expanded master control room at Gravity Medias West...
27/04/2026
Other World Computing Launches OWC Express 4M2 Ultra - Thunderbolt 5 Four-Slot N...
27/04/2026
Back to All News
Netflix announces El sobrino, the new film by Dami n Szifron s...
26/04/2026
Back to All News
Director Yoon Jong-bin Returns with The Generals' (WT), A...
26/04/2026
Back to All News
Nine Queens, Starring Alvaro Morte and Patrick Criado, Starts ...
25/04/2026
Mediagenix Sweeps 2026 NAB Awards With Wins for Product of the Year and Best of ...
25/04/2026
SCHOEPS Microphones Announces Desert Island Boom Set for NAB 2026
Brie Clayton April 24, 2026
0 Comments
Compact modular set ideal for location sound ...
25/04/2026
Berklee Africana Studies Hosts Gospel Extravaganza 2026 The Signature Series event will honor three new inductees to the Berklee Gospel Hall of Fame and celeb...
25/04/2026
Student Spotlight: Siva Maja Gierszewska, who performs under the artist name Siva, shares how she found her songwriting confidence at Berklee.
April 24, 2026...
25/04/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
24/04/2026
Churchill Downs Inc. (CDI) has announced a definitive agreement to acquire the intellectual property of the Preakness Stakes and Black-Eyed Susan Stakes from 1/...
24/04/2026
Daktronics has partnered with DCL (Design Communications, Ltd.) to design, manuf...
24/04/2026
Chyron has announced PRIME Translate, a workflow solution that produces live content simultaneously in multiple languages within the PRIME platform. The system ...
24/04/2026
Eutelsat has announced a new partnership with Co-op Cable, introducing an expand...
24/04/2026
Pitch Dublin, an indoor golf simulation and hospitality venue on Dawson Street i...
24/04/2026
G&D and VuWall have announced two senior leadership appointments, effective Apri...
24/04/2026
Victory , the free sports streaming service from A Parent Media Co. Inc. (APMC), has announced a multi-year agreement to become the exclusive local streaming ho...
24/04/2026
The former business major from Massachusetts has found his home in graphics and bug operation while contributing to live ESPN productions
In the live-sports-vi...
24/04/2026
The Mid-Atlantic Sports Network (MASN) and Spectrum have announced a multiyear carriage agreement making MASN available to Spectrum customers in areas of southe...
24/04/2026
The NFL Draft is rebuilt from the ground up in a new city every year. The three-day fan festival is expected to draw 500,000 or more attendees, with millions fo...
24/04/2026
Diversified has continued expansion of its sports and media capabilities to supp...