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postgraduate thesis: Development of peptide-based inhibitors of YEATS2 YEATS as a novel strategy against non-small cell lung cancer
Title | Development of peptide-based inhibitors of YEATS2 YEATS as a novel strategy against non-small cell lung cancer |
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Authors | |
Issue Date | 2023 |
Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
Citation | Liu, S. [刘莎]. (2023). Development of peptide-based inhibitors of YEATS2 YEATS as a novel strategy against non-small cell lung cancer. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. |
Abstract | Epigenetic proteins that regulate the writing, erasing, and reading of histone posttranslational modifications (PTMs) are emerging drug targets, given their essential roles in normal physiology and disease pathogenesis. YEATS domain represents a new class reader protein that recognizes histone acyl modifications such as acetylation, crotonylation, and benzoylation. The human YEATS domain-containing proteins (i.e., AF9, ENL, GAS41, and YEATS2) are involved in various molecular functions, such as transcription elongation, histone variant deposition, and chromatin remodeling. Dysregulation of the YEATS domain is often implicated in different types of cancers, including acute myeloid leukemia (AML) and non-small cell lung cancer (NSCLC). Considering their therapeutic potential, chemical inhibitors for ENL, AF9, and GAS41 have been developed. However, to date, no inhibitors have been developed targeting YEATS2 despite its crucial role in the ADA Two A-Containing (ATAC) histone acetyltransferase complex for transcription regulation and tumorigenesis of NSCLC.
In Chapter 2, I developed first-in-class inhibitors targeting the YEATS domain of human YEATS2. Guided by the structural analysis of the YEATS2 YEATS-H3K27bz complex, I synthesized peptide-derived inhibitors by replacing the benzoyl group with expanded systems or changing the surrounding residues against the surface contacts outside the Kbz-binding pocket. The subsequent structure-activity relationship study has led to the discovery of a potent inhibitor with 89 nM dissociation constant (Kd) toward YEATS2 in vitro. The further optimization of drug-like properties resulted in a potent, selective, and cellularly active inhibitor named LS-170, which efficiently inhibited the proliferation and colony formation of NSCLC cells.
In Chapter 3, the mechanistic and pharmacological role of LS-170 targeting the YEATS2 YEATS domain in NSCLC was investigated. Photo-cross-linking-based pulldown and fluorescence recovery after photobleaching (FRAP) assays showed LS-170 could selectively engage with endogenous YEATS2 but not other YEATS-containing proteins in cells. Armed with this powerful chemical tool, we detailed the biological response of NSCLC cells to pharmacological YEATS2 disruption. Notably, we discovered that YEATS2 YEATS inhibition is sufficient to selectively suppress YEATS2 target genes, including MCMs, CDC6, CCNE2, TK1, and GINS, a subset of cell division-related genes that are highly amplified in NSCLC. In a xenograft mouse model, LS-170 significantly suppressed the NSCLC tumor growth without apparent toxicity. Collectively, our study provided the first thoroughly characterized inhibitors for the YEATS2 YEATS domain and established the YEATS2 YEATS domain inhibition as a feasible strategy to impair the pathogenic function of YEATS2 in NSCLC.
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Degree | Doctor of Philosophy |
Subject | Lungs - Cancer - Genetic aspects Post-translational modification |
Dept/Program | Chemistry |
Persistent Identifier | http://hdl.handle.net/10722/353370 |
DC Field | Value | Language |
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dc.contributor.author | Liu, Sha | - |
dc.contributor.author | 刘莎 | - |
dc.date.accessioned | 2025-01-17T09:46:07Z | - |
dc.date.available | 2025-01-17T09:46:07Z | - |
dc.date.issued | 2023 | - |
dc.identifier.citation | Liu, S. [刘莎]. (2023). Development of peptide-based inhibitors of YEATS2 YEATS as a novel strategy against non-small cell lung cancer. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. | - |
dc.identifier.uri | http://hdl.handle.net/10722/353370 | - |
dc.description.abstract | Epigenetic proteins that regulate the writing, erasing, and reading of histone posttranslational modifications (PTMs) are emerging drug targets, given their essential roles in normal physiology and disease pathogenesis. YEATS domain represents a new class reader protein that recognizes histone acyl modifications such as acetylation, crotonylation, and benzoylation. The human YEATS domain-containing proteins (i.e., AF9, ENL, GAS41, and YEATS2) are involved in various molecular functions, such as transcription elongation, histone variant deposition, and chromatin remodeling. Dysregulation of the YEATS domain is often implicated in different types of cancers, including acute myeloid leukemia (AML) and non-small cell lung cancer (NSCLC). Considering their therapeutic potential, chemical inhibitors for ENL, AF9, and GAS41 have been developed. However, to date, no inhibitors have been developed targeting YEATS2 despite its crucial role in the ADA Two A-Containing (ATAC) histone acetyltransferase complex for transcription regulation and tumorigenesis of NSCLC. In Chapter 2, I developed first-in-class inhibitors targeting the YEATS domain of human YEATS2. Guided by the structural analysis of the YEATS2 YEATS-H3K27bz complex, I synthesized peptide-derived inhibitors by replacing the benzoyl group with expanded systems or changing the surrounding residues against the surface contacts outside the Kbz-binding pocket. The subsequent structure-activity relationship study has led to the discovery of a potent inhibitor with 89 nM dissociation constant (Kd) toward YEATS2 in vitro. The further optimization of drug-like properties resulted in a potent, selective, and cellularly active inhibitor named LS-170, which efficiently inhibited the proliferation and colony formation of NSCLC cells. In Chapter 3, the mechanistic and pharmacological role of LS-170 targeting the YEATS2 YEATS domain in NSCLC was investigated. Photo-cross-linking-based pulldown and fluorescence recovery after photobleaching (FRAP) assays showed LS-170 could selectively engage with endogenous YEATS2 but not other YEATS-containing proteins in cells. Armed with this powerful chemical tool, we detailed the biological response of NSCLC cells to pharmacological YEATS2 disruption. Notably, we discovered that YEATS2 YEATS inhibition is sufficient to selectively suppress YEATS2 target genes, including MCMs, CDC6, CCNE2, TK1, and GINS, a subset of cell division-related genes that are highly amplified in NSCLC. In a xenograft mouse model, LS-170 significantly suppressed the NSCLC tumor growth without apparent toxicity. Collectively, our study provided the first thoroughly characterized inhibitors for the YEATS2 YEATS domain and established the YEATS2 YEATS domain inhibition as a feasible strategy to impair the pathogenic function of YEATS2 in NSCLC. | - |
dc.language | eng | - |
dc.publisher | The University of Hong Kong (Pokfulam, Hong Kong) | - |
dc.relation.ispartof | HKU Theses Online (HKUTO) | - |
dc.rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works. | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject.lcsh | Lungs - Cancer - Genetic aspects | - |
dc.subject.lcsh | Post-translational modification | - |
dc.title | Development of peptide-based inhibitors of YEATS2 YEATS as a novel strategy against non-small cell lung cancer | - |
dc.type | PG_Thesis | - |
dc.description.thesisname | Doctor of Philosophy | - |
dc.description.thesislevel | Doctoral | - |
dc.description.thesisdiscipline | Chemistry | - |
dc.description.nature | published_or_final_version | - |
dc.date.hkucongregation | 2024 | - |
dc.identifier.mmsid | 991044857814903414 | - |