Structural studies offer how-to guide for designing cancer drugs By revealing how the structure of the PI3K protein changes in cancer cells, Scripps Research scientists point toward ways to target it with drugs.
December 08, 2022
LA JOLLA, CA To design drugs that stall the growth of aggressive cancers, it helps to know the structures of the proteins that are revving the cancers' engines.
In a series of three papers published in Proceedings of the National Academy of Sciences, Scripps Research scientists have illuminated the three-dimensional structure of phosphoinositide 3-kinase alpha (PI3K ), a protein often mutated in cancer cells. Moreover, the research team shed light on how that structure changes with the cancer-associated mutations, paving the way for drugs that could target only the mutated versions.
We hope that these detailed structural findings lead to the discovery of drugs that affect cancer cells but not healthy cells, says senior author Peter Vogt, PhD, a professor in the Department of Molecular Medicine at Scripps Research. That could potentially eliminate the side effects associated with current PI3K drugs.
PI3K plays a central role in cell survival and growth. In healthy cells, the protein is flipped on and off as needed. But in numerous types of cancer including breast, colorectal, endometrial and brain mutations in PI3K make it active all the time, encouraging the unchecked growth of the tumors. Current drugs that aim to put the brakes on PI3K bind to a section of the protein that rarely changes between healthy and mutated versions; this means all the PI3K in the body is shut off. Because of that, these PI3K inhibitors carry a long list of side effects and toxicities.
To solve this problem, you have to make inhibitors that only recognize the mutated versions of PI3K , says Vogt. But to do that, you need structural information about what differentiates mutated, overactive PI3K from normal PI3K .
This is no easy feat: PI3K is a particularly flexible, wiggly protein, so it's difficult to get a single snapshot of its structure. Vogt's group, however, discovered that when PI3K was bound to one of the existing inhibitors, it became more stable. In PNAS papers published in November 2021 and September 2022, they used a type of imaging technique known as cryogenic electron microscopy (cryo-EM) to work out the three-dimensional structure of PI3K . With this knowledge, they first examined the structure of PI3K attached to the inhibitor. Then, to visualize the protein without the inhibitor, they used cross-linking molecules to attach different parts of PI3K to itself, stabilizing the most flexible parts of the protein.
More recently, the research team used the same cryo-EM toolbox to piece together the structure of two mutated versions of PI3K often found in cancer cells. That work, published last month in PNAS, showed how some segments of the mutated PI3K resemble the activated form of PI3K .
There are quite dramatic structural changes, says Vogt. And in the end, the changes essentially mimic the normal activated form of the protein, with the only difference being that it's always in this active structure.
The findings point toward ways to use drugs to shut off this always-on version of PI3K in cancer cells, without turning off healthy PI3K . The key, Vogt says, is that the drugs will need to bind to a different part of the PI3K protein than where the existing PI3K inhibitors bind a part that varies structurally between the healthy and mutated versions of the protein.
His lab group is following-up on this research with additional studies revealing how current drugs change the structure of PI3K .
In addition to Vogt, authors of the studies, Cryo-EM structures of PI3K reveal conformational changes during inhibition and activation, Nanobodies and chemical cross-links advance the structural and functional analysis of PI3K , and Cryo-EM structures of cancer-specific helical and kinase domain mutations of PI3K , include Su Yang, Jonathan R. Hart, Lynn Ueno and Alexandra Quezada of Scripps Research.
The work at Scripps Research was supported by funding from the National Cancer Institute (R35 CA197582 and R50 CA243899).
Cancer Molecular and Cellular Biology Vogt, Peter
North America Stories
05/06/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
05/06/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
05/06/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
05/06/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
05/06/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
05/06/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
05/06/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
05/06/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
05/06/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
05/06/2026
Frequency, the engine powering many of the world's leading streaming television channels, today announced the launch of In-Scene Advertising, a new monetiza...
05/06/2026
Berklee Study Reveals Video Has Become Essential to Music Careers Survey findings show social platforms have become the primary source of music for video cont...
04/06/2026
Sony Electronics is introducing the SRG-AS10, a 4K 60p-compatible PTZ auto-frami...
04/06/2026
This recent grad from Spring, TX, led creative-video output for the Aggies' men's basketball team last season and has been producing video and creating ...
04/06/2026
For the first time at a women's golf major, every player in the field will r...
04/06/2026
Three Panasonic PT-RQ45 40,000-lumen 3-Chip DLP projectors made their first live...
04/06/2026
Bitmovin and Akamai have announced a collaboration with NRJ Group, a French mult...
04/06/2026
Telestream will exhibit at InfoComm 2026 (Booth N7952), demonstrating media work...
04/06/2026
Sony has announced the development of RIALTO 65, a 65mm format image sensor block for the VENICE 2 digital cinema camera, targeting release in the first half of...
04/06/2026
KOKUSAI DENKI Electric America will exhibit at InfoComm 2026 (Booth N8025, June ...
04/06/2026
Bell Media's TSN and RDS are the exclusive Canadian broadcasters of FIFA Wor...
04/06/2026
The Challenge: Receiving Heavy Media Files From Road Games Quickly and ReliablyT...
04/06/2026
MASV, a managed file transfer platform used in broadcast and live sports product...
04/06/2026
NESN has announced the appointment of Fahad Haider as Vice President of Operations and Engineering. Haider returns to NESN, where he previously served as Vice P...
04/06/2026
David J. Halberstam, who spent almost 50 years in sports as a broadcaster and an executive, died June 2 after a years-long battle with brain cancer.
Over his l...
04/06/2026
Although collegiate production programs are tasked with delivering high-quality ...
04/06/2026
California studio, two production trucks, global distribution system are combine...
04/06/2026
New global program empowers and supports storytellers through scriptwriting course and access to industry experts
TikTok and Sundance Institute today announce...
04/06/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
04/06/2026
Bitmovin, a leading provider of video streaming infrastructure, and Akamai, the cybersecurity and cloud computing company that powers and protects business onli...
04/06/2026
American Underground (AU), the Startup Hub of the South and a community of mor...
04/06/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
04/06/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
04/06/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
04/06/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
04/06/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
04/06/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
04/06/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
04/06/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
04/06/2026
NVIDIA and Microsoft Reinvent Windows PCs for the Age of Personal AI
Brie Clayton June 3, 2026
0 Comments
RTX Spark - a 1-Petaflop Superchip, the Full...
04/06/2026
Inside the Peaky Blinders: The Immortal Man Grade
Brie Clayton June 3, 2026
0 Comments
Simone Grattarola discusses shaping the look in DaVinci Resolve...
04/06/2026
Cine Gear Expo Announces 2026 Awards of Excellence Recipients
Brie Clayton June 3, 2026
0 Comments
Ed Lachman ASC, Caleb Deschanel ASC, and M. David M...
04/06/2026
St. Vincents Live with Orchestra Tour to Feature Berklee Alum Ruby Plume Berklee alumni St. Vincent and Ruby Plume will appear on the same bill across seven d...
04/06/2026
Home to cutting-edge sovereign AI infrastructure and robotics innovators, as well as one of the world's most passionate gaming communities, South Korea is o...
04/06/2026
Back to All News
All the Truth in My Lies Coming to Netflix on August 28
Entertainment
04 June 2026
GlobalSpain
Link copied to clipboard
Download the imag...
04/06/2026
Back to All News
Larry Tanz, VP of Content, EMEA, Delivers a Keynote Speech at ...
04/06/2026
Back to All News
Turn Your Living Room into a Stadium With the New FIFA World ...
04/06/2026
Keeping conversations real on LinkedIn Published on Jun 4, 2026 Categories: Product News
LinkedIn Corporate Communications
Share
LinkedIn
Facebook ...
04/06/2026
June's forecast with GeForce NOW: 100% chance of gaming.
GeForce NOW is lining up new adventures for the month, from big-name blockbusters to quirky indies...
03/06/2026
SES and Viva, Mexico's ultra low-cost airline, have launched multi-orbit satellite inflight connectivity on Viva's Airbus aircraft. A total of 60 A320s ...
Structural studies offer how-to guide for designing cancer drugs By revealing how the structure of the PI3K protein changes in cancer cells, Scripps Research scientists point toward ways to target it with drugs.
