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Notch inhibitors 2018-05-16T08:30:23+00:00

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. The NICD can then enter the nucleus where it interacts with other factors, and orchestrates a transcriptional response leading to cell differentiation, proliferation, and survival. Notch target genes have shown to have roles in carcinogenesis and tumor progression.

Advances in sequencing technologies have enabled the discovery of activating Notch mutations in multiple tumor types, including Adenoid Cystic Carcinoma (ACC) and Triple Negative Breast Cancer (TNBC).

AL101 Notch Targeted Therapy (Gamma Secretase Inhibitor)

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 may inhibit
Notch signalling and potentially impede tumor growth.

AL101 has completed phase 1 studies and is advancing in
clinical development with the goal of bringing hope to
new underserved populations.

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

    *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.

  • 02 Notch Activation in Cancer

    In cancer, activation of Notch results in uncontrolled apoptosis (cell death), 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

    *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.

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