Novel inhibitors for Natural Killer/T-cell lymphoma (NKTCL)
The Natural Killer/T-cell lymphoma (NKTCL) is a subtype of Non-Hodgkin’s lymphoma (NHL) which is more prevalent in Asian and Native American populations. Despite the use of multi-agent chemotherapy and involved-field radiotherapy, the outcome of NKTCL treatment remains poor with the 5-year overall survival in the range of 40% and 10% for nasal and non-nasal NKTCL, respectively. In addition, many patients develop resistance to chemotherapy, especially at the late stage.
Janus Kinase 3 (JAK3) belongs to a family of cytoplasmic non-receptor tyrosine kinases that include JAK1, JAK2, JAK3 and TYK2, all of which play a role in different cytokine and growth factor receptor-mediated signaling pathways. Recent studies have identified frequent JAK3 activating mutations in a number of malignancies, including 20-35% in NKTCL, suggesting JAK3 as a novel target for cancer therapy. However, targeting JAK3 selectively with small-molecule inhibitors has been challenging due to the highly conserved amino acid composition of the ATP binding pocket among JAK family members.
This project utilizes well established JAK3 cellular methodologies to (i) determine potency and specificity of selective JAK3 inhibitors (ii) assess pharmacological properties of specific JAK3 inhibitors and (iii) evaluate efficacy of drug-like small molecules in both in-vitro and in-vivo models.
Principal Investigator: Dr ONG Choon Kiat
Institution: National Cancer Centre Singapore
NHIC Ref: NHIC-I2D-1608130