Related Experiment Video

Updated: May 20, 2026

Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
13:22

Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays

Published on: October 23, 2019

AT13148 is a novel, oral multi-AGC kinase inhibitor with potent pharmacodynamic and antitumor activity

Timothy A Yap1, Mike I Walton, Kyla M Grimshaw

  • 1Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, Sutton, United Kingdom.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|July 12, 2012
PubMed
Abstract

Insights

The novel drug AT13148, a multi-AGC kinase inhibitor, effectively blocks cancer cell growth and induces apoptosis. This compound demonstrates potent antitumor activity and a distinct mechanism of action, warranting further clinical investigation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Deregulated phosphatidylinositol 3-kinase (PI3K) pathway signaling via AGC kinases (e.g., AKT, p70S6K, PKA, SGK, ROCK) drives multiple cancers.
  • Simultaneous inhibition of multiple AGC kinases may enhance antitumor activity and reduce clinical resistance compared to targeting single pathway components.

Purpose of the Study:

  • To investigate the pharmacology and antitumor activity of AT13148, a novel oral ATP-competitive multi-AGC kinase inhibitor.
  • To characterize the molecular mechanisms of action of AT13148 using gene expression microarray studies.

Main Methods:

  • Pharmacodynamic and antitumor activity assessment of AT13148 in cancer cell lines and xenograft models.
  • Gene expression microarray analysis to elucidate molecular mechanisms of action.
  • Evaluation of substrate phosphorylation blockade and apoptosis induction in vitro and in vivo.

Main Results:

  • AT13148 effectively inhibited phosphorylation of AKT, p70S6K, PKA, ROCK, and SGK substrates, inducing apoptosis in cancer cells with relevant genetic defects.
  • Demonstrated antitumor efficacy in HER2-positive breast, PTEN-deficient prostate, and PTEN-deficient uterine tumor xenografts.
  • Gene expression studies revealed AT13148 predominantly affects apoptosis genes, contrasting with cell-cycle modulation by selective AKT inhibitors; compensatory feedback loops were observed.

Conclusions:

  • AT13148 is a novel oral multi-AGC kinase inhibitor with significant pharmacodynamic and antitumor effects.
  • AT13148 exhibits a distinct mechanism of action compared to other AKT inhibitors.
  • AT13148 is advancing to a first-in-human Phase I clinical trial.

Related Concept Videos

Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against specific...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
Chemotherapy-Induced Nausea and Vomiting: Neurokinin-1 Receptor Antagonists01:28

Chemotherapy-Induced Nausea and Vomiting: Neurokinin-1 Receptor Antagonists

Neurokinin 1 (NK1) receptors are distributed across the GI tract, vagal afferents, and key CNS regions including the central vomiting center and chemoreceptor trigger zone (CTZ) Chemotherapy agents stimulate enterochromaffin cells in the gastrointestinal (GI) tract to release large amounts of substance P (SP). SP is a neuropeptide released by specific sensory nerves in response to many different stressors, including those in the GI mucosa affected by chemotherapy.  SP binds and activates these...