ELarocque_Dissertation .pdf (7.63 MB)
Targeting Drug-Resistant Cancer-Driver Kinases with Alkynylnicotinamide Compounds
thesisposted on 2021-10-12, 15:04 authored by Elizabeth A LarocqueElizabeth A Larocque
Cancer treatment was revolutionized when imatinib, a protein kinase inhibitor, was approved for the treatment of chronic myeloid leukemia (CML) in 2001. Imatinib increased the five-year survival rate of CML to over 90%. Imatinib is successful because it can selectively target BCR-ABL1, the mutant kinase driver to CML. Since then, there have been over 50 small molecules approved by the FDA to treat various cancers, which are driven by aberrantly expressed or mutated protein kinases. These kinase inhibitors (KIs) target kinases such as KIT (to treat gastrointestinal stromal tumors), EGFR (to treat lung cancer), and MEK (to treat melanoma) and often inhibit the kinases by binding to the ATP binding site or an allosteric site. Despite the successes seen with these approved KIs, responses are often transient. Most patients relapse after only a few months of responding to first and second generation KIs due to mutations to the kinases and/or upregulation of compensatory pathways. For cancer-driver kinases such as BCR-ABL1 or FLT3-ITD, which are oncogenic due to a fusion protein (BCR fused to ABL1) or internal tandem duplication within the juxtamembrane domain (FLT3), relapse can also occur due to the emergence of additional mutations in the kinase domain (a phenomenon termed secondary mutation). For example, secondary mutation (T315I or E255K) in BCR-ABL1 leads to imatinib resistance whereas secondary mutation (F691L or D835Y/V/H) in FLT3-ITD leads to resistance to many first- and second-generation FLT3 inhibitors. Gilteritinib, a recently approved FLT3 inhibitor drug for acute myeloid leukemia (AML) is not effective against AML harboring FLT3-ITD (F691L). Thus, there is a clinical need for novel chemotypes that inhibit drug-resistant kinases, especially those containing secondary mutations.
Many of the FDA-approved kinase inhibitors contain common heterocycles such as quinolines, indazoles, quinazolines, quinazolinones, quinoxalines, and oxindole. The majority of KIs also contain groups that enhance aqueous solubility, such as morpholine and piperazine rings. Additionally, many KIs contain halogen substituents (mainly Cl and F). This thesis introduces novel kinase inhibitors, which contain the less explored isoquinolines, naphthyridines, and pyrido[3,4-b]pyrazine cores. These newly introduced kinase inhibitors potently inhibit drug-resistant ABL1 and FLT3 kinases, harboring secondary mutations, and have the potential for clinical translation against relapsed leukemia.
- Doctor of Philosophy
- West Lafayette