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
Europe Stories
05/01/2027
Worlds first 802.15.4ab-UWB chip verified by Calterah and Rohde & Schwarz to be ...
07/10/2026
Dalet, a leading technology and service provider for media-rich organizations, today announced the latest Long-Term Supported (LTS) release of Dalet Flex. Build...
06/09/2026
June 9 2026, 23:00 (PDT) Dolby and MagentaTV Bring Fans Closer to the FIFA Worl...
04/08/2026
Dalet, a leading technology and service provider for media-rich organizations, t...
23/07/2026
Download Now!
To receive a short case study showcasing Vivid Broadcast's audio setup, please enter the following details:
--
First Name* First Name ...
23/07/2026
RT Commercial has today announced Centra as the official food partner once again of The Traitors Ireland, coming to RT One and RT Player later this year.
Ce...
23/07/2026
RT Commercial today announced Honda as sponsor of Today with David McCullagh RT Radio 1, weekdays 9am 11am.
Broadcasting directly after Morning Ireland in ...
23/07/2026
RT News is pleased to announce Barry Gallagher has been assigned as the new journalist covering news from Cork, Kerry and the wider Southern region
Working al...
22/07/2026
Library now available in Engine Player
Another of Eduardo Tarilonte's popular sample libraries has just been moved over to Engine Audio's Engine Pla...
22/07/2026
All-in-one mic & DSP interface overhauled
Cloudvocal have just refreshed the design of their all-in-one mic, audio interface and DSP processor, introducing ...
22/07/2026
The final boss of the lost dual-op-amp circuit
Electro-Harmonix have just introduced the Deluxe Big Muff Pi 2, which they say offers their latest take on t...
22/07/2026
eds3_5_jq(document).ready(function($) { $(#eds_sliderM519).chameleonSlider_2_1({ content_source:......
22/07/2026
A poisoned spy, a secret war, and a small English city contaminated by a deadly chemical weapon. Available on Sky Documentaries from 4 AugustWednesday 22 July 2...
22/07/2026
Audio at Parity: Comscore Launches Transcript-Level Targeting and Measurement wi...
22/07/2026
Arvato Systems and Lobster Enter into a Partnership and Combine the Integration Platform and Managed Services
Flexible integration solutions for cloud, hybrid...
22/07/2026
RT REPORTS NET SURPLUS OF 22.5 MILLION IN 2025...
22/07/2026
In the Opinion of the Censor airs Monday 27 July at 9.35pm on RT One and RT Player
In the Opinion of the Censor looks at how films for theatrical release wer...
21/07/2026
New research involving a cross-section of Mongolias independent media landscape finds enthusiasm for AI as a tool to improve efficiency, sustainability and resi...
21/07/2026
High-end analogue channel strip boasts plug-in recall
Originally revealed as a prototype back at NAMM 2024, the Channex Studio channel strip represented a b...
21/07/2026
Relies on same DSP as plug-in range
Musik Hack's line-up has been influenced heavily by founder Stan Greene's work as a mixing engineer, and their M...
21/07/2026
Official collaboration with boutique builder Dirty Boy Pedals
Warm Audio have just announced the launch of a new guitar pedal range created in collaboration...
21/07/2026
Rohde & Schwarz showcases broad range of EMC test solutions at EMC SIPI 2026 in ...
21/07/2026
X-Rite Pantone and NIFT Partner to Build Color Management Skills for India's...
21/07/2026
Harmonics cOS Virtualized Broadband Platform and Pearl Remote OLTs Enable Flexible PON Migration, While SeaStar Optical Node Powers Cost-Effective Multi-Gigabit...
21/07/2026
160 hours of Irish storytelling for 2026
KIN and The Walsh Sisters return
RT has today unveiled its most ambitious drama slate ever, with a record-breakin...
20/07/2026
Product range now readily available in the UK
Graph Tech Guitar Labs have just announced the launch of a new UK Online Store that makes it quicker and easie...
20/07/2026
Popular headset gains active noise cancellation
The Maxwell headet was Audeze's first foray into the gaming world, and thanks to its Dolby Atmos compati...
20/07/2026
Monday 20 July 2026
Sky brings free global roaming to millions of loyal custome...
20/07/2026
Red Seat Ventures Announces Introduction of Premium Creator and Podcast Communit...
20/07/2026
FIFA World Cup Final sets new RT Player record as the most-streamed single event in the platform's history
Over 1 million viewers watched live on RT 2 as ...
19/07/2026
Channel strip plug-in gets upgraded
Acustica Audio's vintage-inspired channel strip plug-in has just been treated to an update that expands its tonal ra...
18/07/2026
Captures nine sought-after Fender amps
IK Multimedia's latest TONEX expansion captures a selection of nine rare Brown Panel' Fender amps that were ...
18/07/2026
Latest batch ships alongside firmware update
Since being unveiled at Superbooth 2025, Frap Tools' debut polysynth has been met with widespread praise, a...
17/07/2026
Full engine access with reduced soundset
Sonuscore have steadily been introducing a selection of reduced-cost and free versions of their flagship products r...
17/07/2026
Two new special-edition models revealed
Over the past week, Arturia have launched special-edition versions of both their premium MIDI controller and stage p...
17/07/2026
Original founder now back at the helm
In a message posted on his personal social media accounts, Dirk Ulrich has announced that both Plugin Alliance and Bra...
17/07/2026
From intimate acoustic settings to large-scale festival stages, her focus has remained constant: preserving the true natural voice of the violin in every perfor...
17/07/2026
New and returning series, live festival broadcasts, powerful documentaries and major sporting moments headline RT Radio 1's summer schedule
RT Radio 1 is...
17/07/2026
Up For The Match - Live From Croke Park this Saturday at 8pm on RT One and RT ...
17/07/2026
RT Commercial has today announced DiscoverIreland.ie, as sponsor of The Traitor...
16/07/2026
Media organisations with tested plans for new products, services or revenue models can now apply for grants of up to 30,000 through the Business Innovation Syn...
16/07/2026
A new benchmark in bass enhancement
Described as a new benchmark in bass enhancement , Baby Audio's latest release has been designed to augment the lo...
16/07/2026
Popular library rebuilt in new Orbita Engine
Other Worlds Evolved is the latest of Zero G's sample libraries to be treated to a ground-up rebuild using ...
16/07/2026
Created in collaboration with A. G. Cook
The newest addition to Native Instruments' software collection introduces a new synth created by A. G. Cook, a ...
16/07/2026
Rohde & Schwarz supplies conformance test systems to Marquistech for India's...
16/07/2026
Modern broadcast facilities are no longer confined to a single control room. Production teams are spread across multiple workstations, machine rooms, studios, c...
16/07/2026
Whether you're operating a single control room or managing metering across an entire broadcast facility, having the right information in the right place is ...
16/07/2026
San Jose, CA - July 16, 2026 - Harmonic (NASDAQ: HLIT) today announced a $25,000...
16/07/2026
Modern broadcast facilities are no longer confined to a single control room. Production teams are spread across multiple workstations, machine rooms, studios, c...
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.
