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Orthosteric PI3Kα inhibitors often show limited selectivity, causing adverse effects such as hyperglycemia from wild-type PI3Kα inhibition. Using molecular dynamics simulations and cryo-electron microscopy, the study maps an allosteric network explaining how mutations promote PI3Kα activation. A DNA-encoded library screen and orthosteric-blocking strategy identified RLY-2608, which suppressed tumor growth with minimal insulin impact and produced objective responses in two advanced breast cancer patients without WT PI3Kα-related toxicities.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/discovery-and-clinical-proof-of-concept-of-rly-2608-a-first-in-class-mutant-selective-allosteric-pi3k-inhibitor-that-decouples-antitumor-activity-from-hyperinsulinemia/340904/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/discovery-and-clinical-proof-of-concept-of-rly-2608-a-first-in-class-mutant-selective-allosteric-pi3k-inhibitor-that-decouples-antitumor-activity-from-hyperinsulinemia/340904.png","ImageObject",300,407,{"name":92,"@type":93},"Himbo","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-28","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":44},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why are PI3Kα inhibitors limited in PIK3CA-mutant cancers?","Question",{"text":112,"@type":113},"Current orthosteric PI3Kα inhibitors can lack selectivity and inhibit wild-type PI3Kα, leading to toxicities such as hyperglycemia and dysregulated glucose homeostasis.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How did the researchers identify the inhibitor RLY-2608?",{"text":117,"@type":113},"The work combined molecular dynamics simulations with cryo-electron microscopy to define an allosteric network, then used a DNA-encoded library screen with electron microscopy-optimized constructs and differential enrichment plus an orthosteric-blocking compound.",{"name":119,"@type":110,"acceptedAnswer":120},"What clinical and preclinical effects did RLY-2608 show?",{"text":121,"@type":113},"RLY-2608 inhibited tumor growth in PIK3CA-mutant xenograft models with minimal impact on insulin and elicited objective tumor responses in two patients with advanced hormone receptor–positive breast cancer harboring kinase or helical domain PIK3CA mutations, with no observed wild-type PI3Kα-related toxicities.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},340904,1790640554,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":44,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},687197100911,"https://ap-avatar.wpscdn.com/avatar/a000239b6f1da00475?x-image-process=image/resize,m_fixed,w_180,h_180&k=1785132997149421697","RESEARCH ARTICLE  \nDiscovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia   \nAndreas Varkaris1, Ermira Pazolli2, Hakan Gunaydin2, Qi Wang3, Levi Pierce2, Alessandro A. Boezio2, Artemisa Bulku2, Lucian DiPietro2, Cary Fridrich2, Adam Frost4,5,6, Fabrizio Giordanetto3,  \nErika P. Hamilton7, Katherine Harris8, Michael Holliday2, Tamieka L. Hunter2, Amanda Iskandar2, Yongli Ji9, Alexandre Larivée10, Jonathan R. LaRochelle2, André Lescarbeau2, Fabien Llambi2, Brenda Lormil1,  \nMary M. Mader2, Brenton G. Mar2, Iain Martin2, Thomas H. McLean2, Klaus Michelsen2, Yakov Pechersky3, Erika Puente-Poushnejad2, Kevin Raynor2, Dipali Rogala2, Ramin Samadani2, Alison M. Schram11,  \nKelley Shortsleeves2, Sweta Swaminathan2, Shahein Tajmir12, Gege Tan2, Yong Tang2, Roberto Valverde2, Bryan Wehrenberg2, Jeremy Wilbur2, Bret R. Williams2, Hongtao Zeng2, Hanmo Zhang2, W. Patrick Walters1, Beni B. Wolf2, David E. Shaw3,13, Donald A. Bergstrom2, James Watters2, James S. Fraser6,14,  \nPascal D. Fortin2, and D. Randal Kipp2  \nABSTRACT  PIK3CA (PI3Kα) is a lipid kinase commonly mutated in cancer, including ∼40% of hormone receptor–positive breast cancer. The most frequently observed mutants  \noccur in the kinase and helical domains. Orthosteric PI3Kα inhibitors suffer from poor selectivity leading to undesirable side effects, most prominently hyperglycemia due to inhibition of wild-type (WT) PI3Kα. Here, we used molecular dynamics simulations and cryo-electron microscopy to identify an allosteric network that provides an explanation for how mutations favor PI3Kα activation. A DNA-encoded library screen leveraging electron microscopy-optimized constructs, differential enrichment, and an orthosteric-blocking compound led to the identification of RLY-2608, a first-in-class allosteric mutantselective inhibitor of PI3Kα. RLY-2608 inhibited tumor growth in PIK3CA-mutant xenograft models with minimal impact on insulin, a marker of dysregulated glucose homeostasis. RLY-2608 elicited objective tumor responses in two patients diagnosed with advanced hormone receptor–positive breast cancer with kinase or helical domain PIK3CA mutations, with no observed WT PI3Kα-related toxicities.  \nSIGNIFICANCE: Treatments for PIK3CA-mutant cancers are limited by toxicities associated with the inhibition of WT PI3Kα. Molecular dynamics, cryo-electron microscopy, and DNA-encoded libraries were used to develop RLY-2608, a first-in-class inhibitor that demonstrates mutant selectivity in patients. This marks the advance of clinical mutant-selective inhibition that overcomes limitations of orthosteric PI3Kα inhibitors.  \nSee related commentary by Gong and Vanhaesebroeck, p. 204.  \nSee related article by Varkaris et al., p. 227.  \nINTRODUCTION  \nPhosphoinositide 3-kinases (PI3K) catalyze the conversion of phosphatidylinositol bisphosphate PI(4,5)P2 to phosphatidylinositol-3,4,5-triphosphate, or PIP3 (1). The production of these phospholipids can anchor proteins involved in signal transduction cascades that influence a wide range of cellular processes, including growth and survival (2). Accordingly, in PI3Ks, the enzymatic activity of the catalytic subunit is tightly controlled by a regulatory subunit in a dimeric assembly (3).  \n1Mass General Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts. 2Relay Therapeutics, Inc., Cambridge, Massachusetts. 3D. E. Shaw Research, New York, New York. 4Altos Labs, Institute of Science, San Francisco, California. 5Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California. 6California Institute of Quantitative Biosciences (QB3), University of California San Francisco, San Francisco, California. 7Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee.  \n8MGH/Mass General Cancer Center at Danvers, Danvers, Massachusetts.  \n9Hematology/","cbCaimMGgHK0PcUl","https://ap.wps.com/l/cbCaimMGgHK0PcUl","pdf",16878389,18,"English","# Abstract\n## Significance\n# Introduction","[{\"question\":\"Why are PI3Kα inhibitors limited in PIK3CA-mutant cancers?\",\"answer\":\"Current orthosteric PI3Kα inhibitors can lack selectivity and inhibit wild-type PI3Kα, leading to toxicities such as hyperglycemia and dysregulated glucose homeostasis.\"},{\"question\":\"How did the researchers identify the inhibitor RLY-2608?\",\"answer\":\"The work combined molecular dynamics simulations with cryo-electron microscopy to define an allosteric network, then used a DNA-encoded library screen with electron microscopy-optimized constructs and differential enrichment plus an orthosteric-blocking compound.\"},{\"question\":\"What clinical and preclinical effects did RLY-2608 show?\",\"answer\":\"RLY-2608 inhibited tumor growth in PIK3CA-mutant xenograft models with minimal impact on insulin and elicited objective tumor responses in two patients with advanced hormone receptor–positive breast cancer harboring kinase or helical domain PIK3CA mutations, with no observed wild-type PI3Kα-related toxicities.\"}]","Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia | PDF",1790039480,45]