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Notch inhibitors2019-11-05T13:29:24+00:00

Notch signaling pathway is an oncogenic driver in defined cancers 

Notch signaling pathway is an oncogenic driver in defined cancers

Notch signaling plays an important role during embryonic development and is frequently dysregulated in cancer.

Notch signaling is initiated by activation of one of the four Notch receptors (Notch 1-4) which are transmembrane proteins. Normally, this is achieved when a Notch receptor binds to a Notch ligand on a neighboring cell, an event that triggers proteolytic cleavage cascade resulting in the release of the Notch intracellular domain (NICD) from the membrane by gamma secretase. The NICD then enters the nucleus,interacts with other factors, and orchestrates a transcriptional response leading to cell differentiation, proliferation, and survival. Genes upregulated by Notch signaling were shown to have a role in carcinogenesis and tumor progression.

Advances in sequencing technologies have enabled the discovery of Notch activating mutations in multiple tumor types, including Adenoid Cystic Carcinoma (ACC),Triple Negative Breast Cancer (TNBC) and T-cell Acute Lymphoblastic Leukemia (T-ALL)

Notch Targeted Therapy (Gamma Secretase Inhibitors)

AL101 Notch Targeted Therapy (Gamma Secretase Inhibitor)

Inhibiting activated notch signaling
may impede tumor growth

Ayala is evaluating the potential of a new investigation drug, AL101.

AL101 is a small-molecule that inhibits gamma secretase, an enzyme
which plays a key role in the activation of the Notch signaling pathway
by releasing the Notch intracellular domain (NICD) from the membrane.
In patients with aberrant Notch signaling, AL101 inhibits
Notch signalling and potentially impede tumor growth.

AL101 has completed preclinical and phase 1 studies. A phase 2 study (ACCURACY) for AL101 in patients with adenoid cystic carcinoma (ACC) bearing activated Notch mutations is ongoing.

Interested patients and physicians can contact Ayala Medical for more information at email ClinicalTrials.gov_Accuracy@ayalapharma.com or call +1-857-444-0553.

AL101 Notch inhibitor

  • 01 Notch Pathway In Normal State
  • 02 Notch Activation in Cancer
  • 03 AL101 Inhibits Notch Activation
  • 01 Notch Pathway In Normal State

    Notch signaling plays a key role in normal cell proliferation, differentiation, and development

  • 02 Notch Activation in Cancer

    In cancer, activation of Notch results in uncontrolled proliferation and differentiation processes.

    *Illustration is representative of a classical gain of function (GOF) point mutation. GOF mutations can also occur via translocations, fusions, deletions, and stabilization of NICD.

  • 03 AL101 Inhibits Notch Activation

    AL101 and AL102 bind to and block gamma secretase, preventing cleavage of the Notch receptor and, hence, release of the NICD into the nucleus, which is necessary to initiate the transcription of the Notch target genes; thereby, inhibiting the activation of the Notch pathway

    *Illustration is representative of a classical gain of function (GOF) point mutation. GOF mutations can also occur via translocations, fusions, deletions, and stabilization of NICD.

Preclinical and Clinical Experience

AL101 is an investigational Notch inhibitor in development for oncology indications.

Preclinical studies have shown low nM inhibitory activity for all four Notch receptors (1-4) and robust, broad-spectrum efficacy was seen in traditional and PDX (Patient Derived Xenograft) models, including T-ALL, TNBC, NSCLC, Colorectal and Pancreatic carcinoma.

In phase 1b clinical studies, given once a week by intravenous infusion, the molecule has shown positive PK/PD attributes, sustained inhibition, and was well tolerated with manageable side effects in more than 200 cancer patients.

A phase 2 study (ACCURACY) for AL101 in patients with adenoid cystic carcinoma (ACC) bearing activated Notch mutations has been initiated. Interested patients and physicians can contact the Ayala Physician and Patient Clinical Trial Hotline for more information at +1-857-444-0553 or email ClinicalTrials.gov_Accuracy@ayalapharma.com.

Precision oncology is about getting the right match 

Molecular testing and genomic sequencing have revolutionized our ability to detect oncogenic drivers – activated gene alterations that signal normal healthy cells to rapidly proliferate and become cancerous.

In contrast to the traditional one-strategy-fits-all approach to disease treatment and prevention, which targets a hypothetical “average” patient, the emerging approach of precision oncology strives to develop pinpoint strategies for each and every person’s genomically defined tumor.

By matching the right patient to the right drug, we hope to achieve the promise of precision oncology: deliver better clinical responses and greater benefits for patients.

Be informed