From Probes to Therapeutics: Chemical Biology Studies of Anaplastic Lymphoma Kinase (ALK) and Cereblon
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Powell, Chelsea Elizabeth
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CitationPowell, Chelsea Elizabeth. 2020. From Probes to Therapeutics: Chemical Biology Studies of Anaplastic Lymphoma Kinase (ALK) and Cereblon. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractAlthough there is still discussion surrounding the exact definition of the field, chemical biology is generally described as the development and deployment of a chemical toolbox to manipulate biological systems. The two major overlapping categories that define these chemical tools are probes and drugs.
The rapid development of the field of chemical biology has contributed to the boom in the use of small molecule kinase inhibitors as targeted cancer therapies. Chapters 2 and 3 discuss the development of new classes of compounds that target anaplastic lymphoma kinase (ALK), a clinically relevant lung cancer target, that may provide ways of overcoming tumor resistance, either on their own or through combination therapies with previous ALK inhibitors. Chapter 2 describes published work on the development of the first small molecule degraders that can chemically induce ALK degradation, including in non-small-cell lung cancer (NSCLC), anaplastic large-cell lymphoma (ALCL), and neuroblastoma (NB) cell lines (Powell et al., J Med Chem 2018). These degraders were developed through conjugation of known pyrimidine-based ALK inhibitors, TAE684 or LDK378, and the cereblon (CRBN) ligand pomalidomide. Chapter 3 describes the identification of a potential allosteric ALK inhibitor, which would be the first compound that targets ALK through this mechanism of action. Initial profiling of this compound was promising and indicates that further screening against the theorized allosteric pocket should be performed. Both Chapters 2 and 3 provide proof of concept that a new class of compounds may be used to therapeutically target ALK-positive cancers.
Chapters 4 and 5 discuss studies around the biology of the CRBN E3 ligase, the E3 ligase recruited by the ALK degraders described in Chapter 2. Chapter 4 describes a screening strategy for identifying novel CRBN modulators that can induce protein degradation. We generated a thalidomide analog library by introducing kinase inhibitor scaffolds to lenalidomide and screened the library in MM1.s cells for CRBN dependent antiproliferative activity. Through this method we identified 5 hit compounds that can selectively induce the degradation of GSPT1, a previously identified target of CRBN modulators. Chapter 5 describes the use of small molecule degraders to induce CRBN degradation. We compared degraders that recruited CRBN to itself to degraders that recruited the von-Hippel Lindau (VHL) E3 ligase to CRBN. We determined that a higher degree of selective and potent CRBN degradation could be achieved by recruiting VHL. We present lead selective CRBN degraders, ZXH-4-130 and ZXH-4-137, that may be used as probes to better understand endogenous CRBN biology.
Chapters 6 and 7 describe kinase inhibitor studies around additional therapeutically relevant targets: dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) and tyrosine kinase nonreceptor 2 (TNK2, also known as ACK1), respectively. Chapter 6 describes the identification of the first macrocyclic inhibitors of DYRK1A and Chapter 7 describes high-throughput efforts to optimize lead TNK2 inhibitors from the benzopyrimidodiazepinone scaffold.
Overall, this work fits squarely under the umbrella of chemical biology by demonstrating the development of small molecules as inhibitors, degraders, and modulators for both therapeutic and probe purposes.
Citable link to this pagehttps://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37365125
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