Treating cancers has been one of the greatest challenges of biomedical research in the last few decades. However, the advent of targeted therapy has revolutionized the treatment options for cancer patients. Unlike traditional chemotherapy which are indiscriminately cytotoxic, targeted therapeutics agents are directed towards specific proteins or genes which are crucial for a particular cancer. Kinases, due to their extensive role in several biological processes including cell division, growth, proliferation, angiogenesis, and apoptosis, are often the appropriate ‘targets’ for targeted therapy. Thus, kinase inhibitors have been one of the most widely studied drug classes for cancer therapy, with 61 kinase inhibitors approved by FDA till date.
Although several kinases are widely studied for their role in cancers and explored for therapeutic potential, there is immense room for progress. Firstly, an inhibitor for several of these kinases is yet to be approved for clinical use. Secondly, kinase inhibitors are of various classes, and for many kinases, although inhibitor of a particular class is known, inhibitors of other classes, which could offer clinical benefit, are yet to be discovered. Thirdly, combining targeted therapies with other therapies has shown great promise. Many of these combinations involving kinase inhibitors are yet to be explored.
The work presented in this thesis is directed mainly towards Aurora Kinase B. Drug discovery projects in the last 2 decades targeting Aurora Kinase B resulted in several Aurora B inhibitors. However, none of them are approved for clinical use. Currently, drug discovery and development efforts targeting Aurora B face the following challenges: (1) all the known Aurora B inhibitors are ATP-competitive which bind to the active state of the kinase. There are no inhibitors which are non-ATP-competitive (2) structure-based
drug design and discovery of non-ATP-competitive inhibitors needs structural knowledge of the inactive state of Aurora B which is not yet crystallized (3) most of the Aurora B inhibitors evaluated in clinical trials are associated with the side-effect febrile neutropenia. Although this could be a direct result of inhibition of Aurora Kinases which are involved in mitosis, most of these drugs also inhibit Class III receptor tyrosine kinases, particularly FLT3 and KIT, which are important for normal hematopoiesis.
This work is aimed at addressing these challenges. Since the inactive state of Aurora B is not experimentally determined, we employed computational methods to simulate the inactive conformation from the experimentally determined active conformation. The important structural features during the flip were characterized and the potentially druggable intermediate conformations identified. Also, the interactions and other requirements important for anchoring Aurora B in a particular conformation were identified.
Based on this knowledge, a series of Aurora B inhibitors were designed. Following a cycle of synthesis and enzymatic screening, the structure activity relationship (SAR) was established and the scaffold optimized for Aurora B inhibition. The enzyme kinetics revealed that the lead compound SP-96 shows non-ATP-competitive inhibition, which makes it a first-in-class inhibitor. Also, SP-96 shows > 1200-fold selectivity against FLT3 and KIT, which promises a better side-effect profile. The pharmacophore features responsible for this selectivity was also established. Further, NCI60 data of SP-96 shows that growth inhibition effects of the molecule in certain triple negative breast cancer cell lines, for which targeted therapy is yet to be discovered.
Knowledge of the pharmacophore features responsible for selectivity against tyrosine kinases, mixed with the concept of bioisosterism, was used to explore the activity of pyrrolo[2,3-d]pyrimidine scaffold in tyrosine kinases. After a typical medicinal chemistry cycle of synthesis and screening, a lead compound with activity against RET-wt, RET V804M mutant and RET fusion driven cell line was identified.
In total, the thesis presented herein seeks to fill some of the gaps existing in kinase drug discovery, particularly Aurora Kinase B, with the ultimate aim of improved treatment options for the increasing number of cancer patients in the world.
|Commitee:||Compadre, Cesar, Thakkar, Shraddha, Miller, Grover, Frett, Brendan|
|School:||University of Arkansas for Medical Sciences|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 82/4(E), Dissertation Abstracts International|
|Subjects:||Pharmaceutical sciences, Oncology|
|Keywords:||Aurora Kinase B, Cancer, Kinase inhibitors, Metadynamiccs, RET kinase, Selectivity|
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