
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
Most recent headlines
05/01/2027
Worlds first 802.15.4ab-UWB chip verified by Calterah and Rohde & Schwarz to be ...
04/08/2026
Dalet, a leading technology and service provider for media-rich organizations, t...
04/07/2026
April 7 2026, 19:00 (PDT) Detective Conan: Fallen Angel of the Highway Opens in...
01/06/2026
January 6 2026, 05:30 (PST) Dolby Sets the New Standard for Premium Entertainment at CES 2026
Throughout the week, Dolby brings to life the latest innovatio...
02/05/2026
Dalet, a leading technology and service provider for media-rich organizations, t...
01/05/2026
January 5 2026, 18:30 (PST) NBCUniversal's Peacock to Be First Streamer to ...
23/04/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
23/04/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
23/04/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
23/04/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
23/04/2026
Partnership between ARRI and SmallHD brings new Hi-5 license
Configurable monitor overlays adapt to individual working styles
Supported by SmallHD monitors ru...
23/04/2026
Lighting Master Cronenweth ASC brings a unique look to each grid world with the help of Astera
Jeff Cronenweth on the set of Disney's TRON: ARES. Photo by...
23/04/2026
DP Chloe Smolkin ( The Late Show, Kidz Bop ) joins director Danielle Beckmann and writer/actor Raji Ahsan behind the camera for the heartfelt short comedy Dr...
23/04/2026
Apply now to join the 2026 Producer Delegation to TIFF: The Market 23 April 2026
Screen Australia, in partnership with Ontario Creates, has opened application...
22/04/2026
Solid State Logic is advancing its System T platform with a stronger focus on IP...
22/04/2026
From immersive audio to live streaming, Dolby Laboratories is focused on the fut...
22/04/2026
Shallow depth-of-field cameras have taken the industry by storm. Its debut a han...
22/04/2026
Riedel Communications (Booth C4908) announced that Eastern Kentucky University (...
22/04/2026
The NAB Show is in full swing, and the SVG and SVG Europe editorial teams are chasing down the hottest stories from all over the Las Vegas Convention Center. He...
22/04/2026
Blackmagic Design has announced the URSA Cine 12K LF 100G, a new model in the URSA Cine family adding 100G Ethernet for SMPTE 2110 live production output up to ...
22/04/2026
Celebrating its 40th anniversary, NEP is leaning into hybrid production with the...
22/04/2026
NEP VP, Platform Dan Murphy sits down at the 2026 NAB Show to unpack what NEP P...
22/04/2026
Spotify and the New York Liberty are teaming up to give music and basketball fan...
22/04/2026
New 20-minute documentary explores iconic design The Focusrite Room in Mesa, Arizona, where John Aquilino hosts the Studio Console 005.
In 2025, Focusrite co...
22/04/2026
Offers compact wireless solution for pedalboards
Taiwanese audio brand Cloudvocal have announced the availability of a new pedalboard-friendly wireless syst...
22/04/2026
Latest hybrid sampling/synthesis instrument arrives
Arturia's Augmented series offerings rely on a mixture of sampling and synthesis, allowing users to ...
22/04/2026
Combines three distinct analogue EQ emulations
The latest addition to Acustica Audio's ever-expanding collection of analogue-emulation plug-ins combines...
22/04/2026
Final instalment in vintage-inspired instrument series
Analog Empire: Bass & Lead marks the final instalment in Melda Production's vintage hardware-insp...
22/04/2026
Fuzz pedal joins all-analogue Series A line
Given that Strymons reputation was built on unapologetically digital pedals, it was a little surprising to see t...
22/04/2026
SBS names shortlisted brands for 2026 SBS Media Sustainability Challenge
22 April, 2026
Media releases
National broadcaster also releases its second annual...
22/04/2026
Why Low Band Electronic Warfare Matters...
22/04/2026
The nation unites around football team's World Cup dream
Warsaw, Poland, 20.04.26: Nielsen, a global leader in audience measurement, data, and media intell...
22/04/2026
Warsaw, Poland, 22.04.26: Nielsen, a global leader in audience measurement, data...
22/04/2026
New market intelligence offering gives businesses a clearer view of local consum...
22/04/2026
Glookast Unveils New UX, YouTube and Social Media Connectors, Premiere Panel, Ci...
22/04/2026
Lightcraft Technology to Preview Spark Story at NAB 2026 with Interactive Previs...
22/04/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
22/04/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
22/04/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
22/04/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
22/04/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
22/04/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
22/04/2026
22 Apr 2026
VEON's Banglalink to Bring Starlink Mobile to Customers in Bangladesh Bangladesh becomes the third market where VEON and Starlink Mobile partne...
22/04/2026
U have unveiled exclusive first-look images for their six-part police thriller Hit Point, starring Nick Blood (Day of the Jackal) and BAFTA nominee Saffron Hock...
22/04/2026
What can I watch on UKTV and stream on U this week?
This week on UKTV and the free streaming service U, viewers can watch a range of new and returning programm...
22/04/2026
Wednesday 22 April 2026
Sky announces fifth year of WNT Fund with 30,000 bursa...
22/04/2026
Back to All News
This Earth Day, Discover the Sustainable Productions Behind Our Films and Series
Emma Stewart, Ph.D.
Netflix Sustainability Officer
Enterta...
22/04/2026
The move from Retail Media to Commerce Media is about broadening the scope of th...
22/04/2026
April 22 2026, 07:00 (PDT) Dolby and BMW Bring Dolby Atmos to the BMW 7 Series,...
22/04/2026
RT Documentary On One 7-part series breaks US market for first time
RT Programme Sales has announced its first deal with a US distribution partner for its 7-...