Related Experiment Video

Updated: May 9, 2026

Scaled-Up Preparation of an Intermediate of Upatinib, ACT051-3
08:36

Scaled-Up Preparation of an Intermediate of Upatinib, ACT051-3

Published on: April 7, 2023

AZD1480: a phase I study of a novel JAK2 inhibitor in solid tumors

Elizabeth R Plimack1, Patricia M Lorusso, Patricia McCoon

  • 1Fox Chase Cancer Center, Temple Health, Philadelphia, Pennsylvania 19111, USA. elizabeth.plimack@fccc.edu

The Oncologist
|July 13, 2013
PubMed
Abstract

Insights

AZD1480, a JAK1/2 inhibitor, showed dose-dependent pharmacokinetics and pSTAT3 inhibition in solid tumor patients. However, neurological toxicities led to development discontinuation.

Area of Science:

  • Oncology
  • Pharmacology
  • Immunology

Background:

  • AZD1480 is a novel Janus-associated kinase 1 and 2 (JAK1/2) inhibitor.
  • Solid tumors represent a significant area of unmet medical need.

Purpose of the Study:

  • To evaluate the safety and tolerability of AZD1480 as monotherapy in patients with solid tumors.
  • To characterize the pharmacokinetic and pharmacodynamic profile of AZD1480.

Main Methods:

  • Phase I clinical study involving 38 patients with advanced malignancies.
  • Dosing regimens included 10-70 mg once daily (QD) and 20-45 mg twice daily (b.i.d.).
  • Pharmacokinetic (PK) and pharmacodynamic (PD) analyses were performed, including pSTAT3 inhibition in granulocytes.

Main Results:

  • AZD1480 exhibited rapid absorption and elimination with dose-dependent exposure up to 50 mg.
  • Pharmacodynamic analysis showed maximum phosphorylated STAT3 (pSTAT3) inhibition at higher doses, reaching 56% at 70 mg QD.
  • Dose-limiting toxicities (DLTs) included reversible neurological adverse events such as dizziness, anxiety, and hallucinations.

Conclusions:

  • The exact cause of DLTs (JAK inhibition vs. off-target effects) remains undetermined.
  • Development of AZD1480 was discontinued due to unusual DLTs and lack of clinical activity.

More Related Videos

Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays07:42

Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays

Published on: September 19, 2018

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors12:40

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

Published on: December 7, 2014

Related Concept Videos

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...
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...
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...
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
Treatment Resistent Cancers02:56

Treatment Resistent Cancers

Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
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...