Discovery of FLT3 inhibitors for the treatment of acute myeloid leukemia

Grimm, S.H. (2019)

Doctoral Thesis

The disease acute myeloid leukemia (AML) is characterized by fast progression and low survival rates. Fms-like tyrosine kinase 3 (FLT3) receptor mutations have been identified as a driver mutation in cancer progression in a subgroup of AML patients. Clinical trials have shown emergence of drug resistant mutants, emphasizing the ongoing need for new chemical matter to enable the treatment of this disease. This thesis describes the discovery and evaluation of new chemical series of FLT3 inhibitors and furthermore employs label-free chemical proteomics techniques to evaluate new and existing FLT3 inhibitors for their cellular kinase off-target profile.

• Kinase
• FLT3
• Kinase inhibitor
• Small molecule inhibitors
• Acute myeloid leukemia
• Drug discovery
• Chemical proteomics

• All authors: Grimm, S.H.
• Supervisor: Stelt, M. van der; Neefjes, J.
• Committee: Boeckel, C.A.A. van; Heitman, L.H.; Marel, G.A. van der; Orru, R.V.A; Overkleeft, H.S.; Westen, .G.J.P. van; Wrodnigg, T.
• Qualification: Doctor (dr.)
• Awarding Institution: Leiden Institute of Chemistry, Faculty of Science, Leiden University
• Date: 2019-02-20
• Sponsorship: Cancer Drug Discovery Initiative (CDDI) is acknowledged for funding