ORCID

https://orcid.org/0000-0001-8149-8418

Keywords

PROTACs, SOS1 Degraders Design and Synthesis, KRAS-Mutant Colorectal Cancer, Oxidative Dearomatization, Spirocyclic Frameworks, Towards Total Synthesis of Magellaninone

Abstract

This dissertation focuses on the degradation of SOS1, a guanine nucleotide exchange factor upstream of KRAS, as an alternative therapeutic target for KRAS‑mutant colorectal cancer (CRC). Guided by crystal structures of SOS1 and cereblon, we designed and synthesized a series of PROTACs based on quinazoline‑linker‑lenalidomide hybrids. Among these, the lead degrader induced up to 92% degradation of SOS1 in CRC cell lines and patient‑derived organoids (PDOs), with excellent specificity. In parallel, an AICAR‑derived PROTAC targeting the transmembrane oncoprotein MUC1‑CT in EGFR‑mutant lung cancer achieved time‑dependent and partial target degradation, establishing complementary chemical tools to probe intracellular signaling and degrader mechanisms of action. These findings support PROTAC-mediated protein degradation as a powerful strategy to modulate oncogenic signaling pathways in cancer. In the second part of the dissertation, we developed an efficient and stereoselective method to construct spiro[4.5]cyclohexadienone scaffolds bearing an all-carbon quaternary center, using oxidative dearomatization as the key step. This methodology, combining asymmetric Michael addition, in situ aldehyde reduction, TES deprotection, and K₃[Fe(CN)₆] oxidative dearomatization, enabled the synthesis of a wide range of spirocyclic scaffolds with high diastereo- and enantioselectivity. This methodology was further applied towards the total synthesis of the Lycopodium alkaloid magellaninone, in which oxidative dearomatization served as the key step for constructing the tetracyclic natural product.

Completion Date

2025

Semester

Fall

Committee Chair

Yuan, Yu

Degree

Doctor of Philosophy (Ph.D.)

College

College of Sciences

Department

Chemistry

Format

PDF

Identifier

DP0029758

Document Type

Thesis

Campus Location

Orlando (Main) Campus

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