Wednesday, April 8, 2015

Drugs in Clinical Pipeline: CUDC-101

CUDC-101 [7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamideis a novel molecule which simultaneously inhibits histone deacetylase (HDAC) and the receptor kinases epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) in cancer cells - all of which are overexpressed in many cancersCUDC-101, currently being developed by Curis, Inc., and was in Phase I trail for the common type of especially aggressive head and neck cancer that is not caused by the human papilloma virus (HPV-) but rather by tobacco or alcohol.

Strengthened by its integrated histone deacetylase inhibition, CUDC-101 synergistically blocked key regulators of EGFR/HER2 signaling pathways, also attenuating multiple compensatory pathways, such as AKT, HER3, and MET, which enable cancer cells to escape the effects of conventional EGFR/HER2 inhibitors.  It potently blocks the receptor tyrosine kinases EGFR (aka HER1) and HER2 (IC50s = 2.4 and 16.4 nM, respectively). CUDC-101 also inhibits the activity of class I and class II HDACs at nanomolar concentrations (e.g., IC50s = 4.5, 12.6, 13.2, and 11.4 nM for HDAC1, 2, 4, and 5, respectively). It has only weak effects on over 60 other kinases when tested at 5 ┬ÁM [1].

Cancer cells that have acquired resistance to single-target EGFR inhibitors through upregulation of AXL or loss of E-cadherin remain sensitive to CUDC-101, which inhibits MET- and AXL-mediated signaling, restores E-cadherin expression, and reduces cell migration. CUDC-101 also efficiently inhibited the proliferation of MET-overexpressing non-small cell lung cancer and gastric cancer cell lines and inhibited the migration and invasion of invasive tumor cells. Taken together, these results suggest that coupling HDAC and HER2 inhibitory activities to an EGFR inhibitor may potentially be effective in overcoming drug resistance and preventing cancer cell migration [2].

Phase I

In the phase 1 trial CUDC-101 was combined with the standard of care for treatment of head and neck cancer, which includes the chemotherapy drug cisplatin and radiation. Specifically, the study was performed in 12 medium- to high-risk head and neck cancer patients. At 18 months median follow up, one patient's cancer had worsened, two had died, and nine remained free of disease. Testing of blood and tumor samples showed that CUDC-101 had indeed inhibited the action of EGFR, HDAC and HER2. Although the MTD was identified, a high rate of dose-limiting toxicity (DLT)-independent discontinuation of CUDC-101 suggests a need for alternate schedules or routes of administration [4].

1. Lai, C. J.; et. al. CUDC-101, a multitargeted inhibitor of histone deacetylase, epidermal growth factor receptor, and human epidermal growth factor receptor 2, exerts potent anticancer activity. Cancer Res 2010, 70(9), 3647-3656.
2. Wang, J.; et. al. Potential advantages of CUDC-101, a multitargeted HDAC, EGFR, and HER2 inhibitor, in treating drug resistance and preventing cancer cell migration and invasion. Mol Cancer Ther 2013, 12(6), 925-936.
3. Cai, X.; et. al. Discovery of 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide (CUDc-101) as a potent multi-acting HDAC, EGFR, and HER2 inhibitor for the treatment of cancer. J Med Chem 2010, 53(5), 2000-2009.
4. Galloway, T. J.; et. al. A Phase I Study of CUDC-101, a Multitarget Inhibitor of HDACs, EGFR, and HER2, in Combination with Chemoradiation in Patients with Head and Neck Squamous Cell Carcinoma. Clin Cancer Res 2015, 21(7), 1566-1573.