Peptide Therapeutics Targeting the Estrogen Receptor Alpha in Breast Cancer
Disciplines
Biochemistry | Biochemistry, Biophysics, and Structural Biology | Medicinal-Pharmaceutical Chemistry
Abstract (300 words maximum)
Breast Cancer (BC) is one of the most prevalent cancer types around the globe and the second leading causes of death (20.6%) in USA. According to CDC, in 2019, there are 264,121 cases reported in females for breast cancer in USA, which is significantly higher than the lung (221,097) and colorectal (142,462) cancers. Hormone receptor positive represents the vast majority (60–80%) in breast cancer. Estrogen receptor alpha (ERα), a nuclear receptor and ligand-activated transcription factor, plays pivotal roles in treatment and prevention of the majority of BC. ERα has five distinct domains: activation function domains (AF-1 and AF-2), DNA-binding domain (DBD), hinge (H) and ligand-binding domain (LBD); which is part of AF-2). The most important part of LBD is helix 12, which acts as a molecular switch between the active and inactive conformation of the receptor.
In recent years, somatic mutations in the LBD region of ESR1 gene were identified in patients who previously received the endocrine treatment. These mutations lead to constitutive ERα activity and lessen hormonal therapy efficacy. E380Q, L536Q, Y537S, Y537C, Y537N, and D538G mutations are frequently observed and highly resistive to the endocrine treatment. Tamoxifen and fulvestrant are currently available for endocrine treatment. Besides small molecules drug, peptide therapeutics are thus gaining increasing popularity as they are easy to synthesis, highly selective and have fewer side effects. We synthesized two known peptides which inhibit the ESR1, including AB:3 and AB:4 using Fmoc solid state peptide synthesis (SSPS) and characterize them by liquid chromatography and mass spectrometry. For AB:3, the most intense peak observed at m/z 950.00 corresponds to [M+3H]3+ whereas for AB:4 peptide the most intense peak detected at m/z 595.00, respectively. These results showed that the synthesis of these peptides is successful. Biological assay will be used to evaluate the efficacy of these peptides.
Academic department under which the project should be listed
CSM - Chemistry and Biochemistry
Primary Investigator (PI) Name
Mohammad A. Halim
Peptide Therapeutics Targeting the Estrogen Receptor Alpha in Breast Cancer
Breast Cancer (BC) is one of the most prevalent cancer types around the globe and the second leading causes of death (20.6%) in USA. According to CDC, in 2019, there are 264,121 cases reported in females for breast cancer in USA, which is significantly higher than the lung (221,097) and colorectal (142,462) cancers. Hormone receptor positive represents the vast majority (60–80%) in breast cancer. Estrogen receptor alpha (ERα), a nuclear receptor and ligand-activated transcription factor, plays pivotal roles in treatment and prevention of the majority of BC. ERα has five distinct domains: activation function domains (AF-1 and AF-2), DNA-binding domain (DBD), hinge (H) and ligand-binding domain (LBD); which is part of AF-2). The most important part of LBD is helix 12, which acts as a molecular switch between the active and inactive conformation of the receptor.
In recent years, somatic mutations in the LBD region of ESR1 gene were identified in patients who previously received the endocrine treatment. These mutations lead to constitutive ERα activity and lessen hormonal therapy efficacy. E380Q, L536Q, Y537S, Y537C, Y537N, and D538G mutations are frequently observed and highly resistive to the endocrine treatment. Tamoxifen and fulvestrant are currently available for endocrine treatment. Besides small molecules drug, peptide therapeutics are thus gaining increasing popularity as they are easy to synthesis, highly selective and have fewer side effects. We synthesized two known peptides which inhibit the ESR1, including AB:3 and AB:4 using Fmoc solid state peptide synthesis (SSPS) and characterize them by liquid chromatography and mass spectrometry. For AB:3, the most intense peak observed at m/z 950.00 corresponds to [M+3H]3+ whereas for AB:4 peptide the most intense peak detected at m/z 595.00, respectively. These results showed that the synthesis of these peptides is successful. Biological assay will be used to evaluate the efficacy of these peptides.