Targeting Mutant NT5C2 in Relapsing Acute Lymphoblastic Leukemia

Technology Overview

Researchers at NYU have identified an interesting drug target for relapsing acute lymphoblastic leukemia (ALL), NT5C2, where patient samples led to the identification of gain‑of‑function mutations in this enzyme driving resistance to a certain class of first-line chemotherapy. To expand, the target validation in this project is very rational with a straightforward mechanism of action, a druggable target, validation in both animal and human samples, clear patient stratification approach, and another academic group independently identified the same mechanism of action. Additionally, many tools and collaborators are focused on NT5C2 enzymology, animal models, and clinical samples. Using a CRO partner, researchers completed assay development and an HTS with a 250k compound library, with an ultimate goal to identify small molecule inhibitors selective for the mutant, relapse-specific form of the target. Based on the HTS hits, we used an SAR-by-catalog approach and have identified a few lead compounds with excellent inhibitory properties (IC50s in the high nM range).

ALL affects about 6,000 new cases each year in the US with about 10% relapsing with dismal outcomes. About a quarter of those relapse due to the mechanism being targeted (only a few hundred patients a year in the US, and likely a few thousand worldwide). However, it is also possible to expand the patient target population were the future therapeutic to be administered prophylactically after first line chemo but before clinical relapse presents itself, especially given the biomarker work the lab is conducting for early identification of mutant clones in blood. If the lab can develop a selective, safe, and efficacious agent, this project could be very attractive as a rare disease drug, increasing the likelihood that its clinical trials will be supported by non-profits such as Leukemia and Lymphoma Society, and increasing the potential for a pediatric rare disease voucher that can be used by pharmaceutical companies for acceleration of other pipeline assets (and have historically been sold by smaller companies at a range of $70M-$350M). In parallel, there are a few papers that seem to suggest that increased activity of NT5C2 also plays a role in drug resistance and reduced survival in other hematological-oncology indications such as AML, and the lab is open to testing efficacy in that space as well.

Benefits

• Lead compounds identified with IC50s in the high nm to low µm range
  
• Researchers completed assay development and an HTS with a 250,000 compounds library
• Rare disease drug potential
  
• Increasing the potential for a pediatric rare disease review by the FDA, leading to accelerated time to market
• Potential expansion of patient target population
  
• The target described here is likely to be of interest in other forms of leukemia, such as AML and CML

Applications

The treatment and prevention of relapsing acute lymphoblastic leukemia

Stage of Development

High-throughput screening, hit validation and SAR-by-catalog completed Lead compounds identified

IP Status

• US010745759B2
  
• Provisional patent pending on composition of matter claims for NT5C2 inhibitors