AP26113
Encyclopedia
AP26113 is a small-molecule targeted cancer therapy
, developed by ARIAD Pharmaceuticals
, Inc. AP26113 has exhibited activity as a potent dual inhibitor of anaplastic lymphoma kinase (ALK)
and epidermal growth factor receptor
(EGFR). This compound targets a unique genetic feature of cancer cells and ARIAD has begun a Phase 1/2 clinical trial of AP26113 based on patients’ molecular diagnoses in September 2011.
ALK was first identified as a chromosomal rearrangement in anaplastic large cell lymphoma
(ALCL). Genetic studies indicate that abnormal expression of ALK is a key driver of certain types of non-small cell lung cancer (NSCLC) and neuroblastoma
s, as well as ALCL. Since ALK is generally not expressed in normal adult tissues, it represents a highly promising molecular target for cancer therapy.
Epidermal growth factor receptor
(EGFR) is another validated target in NSCLC. Additionally, the T790M “gatekeeper” mutation is linked in approximately 50 percent of patients who grow resistant to first-generation EGFR inhibitors While second-generation EGFR inhibitors are in development, clinical efficacy has been limited due to toxicity thought to be associated with inhibiting the native (endogenous or unmutated) EGFR. A therapy designed to target EGFR, the T790M mutation but avoiding inhibition of native EGFR is another promising molecular target for cancer therapy.
In 2011, ARIAD announced preclinical studies showing that AP26113 potently inhibited activated EGFR or its T790M mutant, both in cell culture and in mouse tumor models following once daily oral dosing. Importantly, the effective oral doses in these preclinical models were similar to those previously shown to be effective in resistant ALK models. When tested against the native form of EGFR, AP26113 lacked activity, indicating a favorable selectivity for activated EGFR. These data were presented at the International Association for the Study of Lung Cancer (IASLC) 14th World Conference on Lung Cancer
Targeted therapy
Targeted therapy is a type of medication that blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with rapidly dividing cells...
, developed by ARIAD Pharmaceuticals
ARIAD Pharmaceuticals
ARIAD Pharmaceuticals, Inc. is a small pharmaceutical company working on cancer drugs. The company is located in Cambridge, Massachusetts. It was established in 1991 by Larry Bock, David Blech and Dr. Harvery Berger...
, Inc. AP26113 has exhibited activity as a potent dual inhibitor of anaplastic lymphoma kinase (ALK)
ALK inhibitor
ALK inhibitors are potential anti-cancer drugs that act on tumours with variations of anaplastic lymphoma kinase such as an EML4-ALK translocation.-EML4-ALK:About 7% of Non-small cell lung carcinomas have EML4-ALK translocations....
and epidermal growth factor receptor
Epidermal growth factor receptor
The epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands...
(EGFR). This compound targets a unique genetic feature of cancer cells and ARIAD has begun a Phase 1/2 clinical trial of AP26113 based on patients’ molecular diagnoses in September 2011.
ALK was first identified as a chromosomal rearrangement in anaplastic large cell lymphoma
Anaplastic large cell lymphoma
Anaplastic large-cell lymphoma is a type of non-Hodgkin lymphoma that features in the World Health Organisation classification of lymphomas.Its name derives from anaplasia and large-cell lymphoma.-Signs and symptoms:...
(ALCL). Genetic studies indicate that abnormal expression of ALK is a key driver of certain types of non-small cell lung cancer (NSCLC) and neuroblastoma
Neuroblastoma
Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence of about 650 cases per year in the US , and 100 cases per year in the UK . Close to 50 percent of neuroblastoma cases occur in children younger than two years old...
s, as well as ALCL. Since ALK is generally not expressed in normal adult tissues, it represents a highly promising molecular target for cancer therapy.
Epidermal growth factor receptor
Epidermal growth factor receptor
The epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands...
(EGFR) is another validated target in NSCLC. Additionally, the T790M “gatekeeper” mutation is linked in approximately 50 percent of patients who grow resistant to first-generation EGFR inhibitors While second-generation EGFR inhibitors are in development, clinical efficacy has been limited due to toxicity thought to be associated with inhibiting the native (endogenous or unmutated) EGFR. A therapy designed to target EGFR, the T790M mutation but avoiding inhibition of native EGFR is another promising molecular target for cancer therapy.
Pre-Clinical results
In 2010, ARIAD announced results of preclinical studies on AP26113 showing potent inhibition of the target protein and of mutant forms that are resistant to the first-generation ALK inhibitor, which currently is in clinical trials in patients with cancer. ARIAD scientists presented these data at the annual meeting of the American Association for Cancer Research (AACR) in Washington, D.C. in AprilIn 2011, ARIAD announced preclinical studies showing that AP26113 potently inhibited activated EGFR or its T790M mutant, both in cell culture and in mouse tumor models following once daily oral dosing. Importantly, the effective oral doses in these preclinical models were similar to those previously shown to be effective in resistant ALK models. When tested against the native form of EGFR, AP26113 lacked activity, indicating a favorable selectivity for activated EGFR. These data were presented at the International Association for the Study of Lung Cancer (IASLC) 14th World Conference on Lung Cancer