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OHSU # 3001 — Anti-cancer compounds with improved cardiac safety and drug resistance profiles

Summary

Tyrosine kinase inhibitors are effective targeted anti-cancer therapeutics, but currently available inhibitors have limitations due to drug resistance and cardiotoxic effects. Oregon Health & Science University researchers have developed a class of kinase inhibitors with an improved cardiovascular safety profile and the potential to overcome drug resistance.

Technology Overview

Chronic myeloid leukemia (CML) and acute lymphoblastic leukemia are both associated with the oncogene BCR-ABL, and tyrosine kinase inhibitors targeting this oncogene are first-line treatments for these cancers. However, current TKIs have adverse cardiovascular effects and many patients demonstrate drug resistance. The laboratory of Dr. Sanjay Malhotra has taken a structurally-guided approach to design a novel class of TKI inhibitors with the following properties:

  • Highly potent anti-tumor activity, with IC50s in the low nanomolar range.
  • Effective against wildtype BCR-ABL and clinically relevant mutations such as T314I, F317L, E255K and Y253F.
  • Improved cardiovascular safety profile up to 10 µM, as determined by iPSC-cardiomyocyte (iPSC-CM) screening.
  • Comparable efficacies to ponatinib and durable tumor regression in the K-562 xenograft model in mice with oral administration.
  • Utility for a wide range of cancers demonstrating BCR-ABL mutations, including chronic myeloid leukemia, acute lymphoblastic leukemia, and a variety of solid tumors.

Publications

Pandrala M, et al., Designing Novel BCR-ABL Inhibitors for Chronic Myeloid Leukemia with Improved Cardiac Safety. J Med Chem. 2022 Aug 25;65(16):10898-10919. Link

Hnatiuk AP, et al. Reengineering Ponatinib to Minimize Cardiovascular Toxicity. Cancer Res. 2022 Aug 3;82(15):2777-2791. Link

Licensing Opportunity

This technology is available for licensing.

 

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