Blockade of Oncogenic NOTCH1 with the SERCA Inhibitor CAD204520 in T Cell Acute Lymphoblastic Leukemia

Area of Science:

• Biochemistry
• Oncology
• Pharmacology

Background:

• Gain-of-function NOTCH1 mutations drive Notch-dependent cancers.
• SERCA (sarco/endoplasmic reticulum calcium ATPase) is a therapeutic target for these mutations.
• Existing SERCA inhibitors face challenges with toxicity.

Purpose of the Study:

• To characterize CAD204520, a novel small molecule SERCA inhibitor.
• To evaluate CAD204520's preferential targeting of mutated NOTCH1.
• To assess CAD204520's efficacy and safety in preclinical cancer models.

Main Methods:

• Small molecule synthesis and characterization.
• In vitro assays to assess NOTCH1 protein targeting.
• In vivo xenograft studies in T-cell acute lymphoblastic leukemia (T-ALL) models.
• Assessment of cardiac toxicity.

Main Results:

• CAD204520 exhibits improved drug-like properties and reduced Ca2+ toxicity compared to thapsigargin.
• CAD204520 preferentially inhibits mutated NOTCH1 over wild-type NOTCH1.
• CAD204520 suppresses NOTCH1-mutated leukemic cells in a T-ALL xenograft model without cardiac toxicity.
• Efficacy was observed in models with NOTCH1 PEST domain mutations.

Conclusions:

• CAD204520 is a promising SERCA inhibitor for Notch-dependent cancers.
• This compound offers a safer therapeutic window by reducing off-target toxicity.
• The findings support SERCA inhibitors for T-ALL, mantle cell lymphoma (MCL), and chronic lymphocytic leukemia (CLL).