A small-molecule PI3Kα activator for cardioprotection and neuroregeneration

Abstract

Harnessing the potential beneficial effects of kinase signalling through the generation of direct kinase activators remains an underexplored area of drug development 1 – 5 . This also applies to the PI 3-kinase (PI3K) signalling pathway, which has been extensively targeted by inhibitors for conditions with PI3K overactivation, such as cancer and immune dysregulation. Here we report on the discovery of UCL-TRO-1938 (further referred to as 1938), a small molecule activator of the PI3Kα isoform, a critical effector of growth factor signalling. 1938 allosterically activates PI3Kα through a unique mechanism, by enhancing multiple steps of the PI3Kα catalytic cycle, and causes both local and global conformational changes in the PI3Kα structure. This compound is selective for PI3Kα over other PI3K isoforms and multiple protein and lipid kinases. It transiently activates PI3K signalling in all rodent and human cells tested, resulting in cellular responses such as proliferation and neurite outgrowth. In rodent models, acute treatment with 1938 provides cardioprotection from ischaemia reperfusion injury and, upon local administration, enhances nerve regeneration following nerve crush. This study identifies a unique chemical tool to directly probe PI3Kα signalling and a novel approach to modulate PI3K activity, widening the therapeutic potential of targeting these enzymes, through short-term activation for tissue protection and regeneration. Our findings illustrate the potential of activating kinases for therapeutic benefit, a currently largely untapped area of drug development.

Insight into Janus kinases specificity: From molecular architecture to cancer therapeutics

“…Cysteine‐targeting covalent design has achieved great success in the field of kinase inhibitors, 256–258 such as neratinib, 259–261 afatinib, 262–265 dacomitinib, 266–268 osimertinib 269,270 and rociletinib 271 targeting Epidermal Growth Factor Receptor (EGFR‐C797), ibrutinib, 271 acalabrutinib, 272 and poseltinib 273 targeting Bruton's Tyrosine Kinase (BTK‐C481). Moreover, cysteine‐targeting covalent inhibitors have also been extensively studied in other kinases, including Fms‐like tyrosine kinase 3 (FLT3), 274 Extracellular‐regulated kinase 1/2 (ERK1/2), 275 TGF beta‐activated Kinase 1 (TAK1), 276 Phosphoinositide 3‐kinase α (PI3Kα), 277 and others. It is worth mentioning that two recently approved covalent drugs, adagrasib 278 and sotorasib, 279 specifically target Kirsten rats arcomaviral oncogene homolog (KRAS) G12C, which has traditionally been considered an undruggable target.…”

An emerging spectrum of therapeutic targets for Alzheimer's disease

“…UCL‐TRO‐1938, termed 1938, is a small molecule selective activator of PI3Kα, which is a major cellular effector of growth factor signaling. In rodent models, 1938 rapidly and briefly allosterically activates PI3Kα signaling 22 . The cellular result in neurons is proliferation, neurite outgrowth and regeneration after nerve crush injury.…”

“…The potential benefits of selectively enhancing the activity of kinase signaling pathways have only recently been explored as a means of drug development in AD. 22 UCL-TRO-1938, termed 1938, is a small molecule selective activator of PI3Kα, which is a major cellular effector of growth factor signaling. In rodent models, 1938 rapidly and briefly allosterically activates PI3Kα signaling.…”

“…In rodent models, 1938 rapidly and briefly allosterically activates PI3Kα signaling. 22 The cellular result in neurons is proliferation, neurite outgrowth and regeneration after nerve crush injury.…”

A strategy to disentangle direct and indirect effects on (de)phosphorylation by chemical modulators of the phosphatase PP1 in complex cellular contexts

“…Chemical modulators, in particular activators, of enzymes have become of great interest to study the respective enzymes and to target decreased enzymatic function in disease. [1][2][3][4][5] Nevertheless, activators are still rather rare, and enzyme activation can have multiple downstream effects that are difficult to assess comprehensively, complicating the interpretation of enzyme activator treatments. 6 This is particularly relevant when activating a ubiquitous enzyme such as protein phosphatase-1 (PP1), which has shown promise for alleviating cardiomyopathy phenotypes.…”