Small drug inhibitors Flashcards
What is a small drug inhibitor?
A non biological molecule made in a chemistry lab. Antagonist molecule that targets a signaling pathway.
What is an example of using a small drug inhibitor?
HIF1 alpha in hypoxia or tyrosine kinase in cancer cells. Targeted therapies such as monoclonal antibodies for immunotherapy or chemotherapy.
How can they be used in combination with current treatment?
Limit side effect and enhance the effect of drug.
How can they be used in cancer?
To target the microenvironment and physiological stress associated with cancers.
What are some examples of approved cancer drugs that target EGFR and VEGF?
Cetuximab, trastuzumab, bevacizumab, rituximab.
What are some examples of drugs that are used to treat cancer that target TK and VEGF?
Gefitinib, erlotinib, sunitinib
What are the different categories of monoclonal antibodies?
Murine, chimeric, humanized and human.
What is the mechanism of small molecule inhibitors and monoclonal antibodies for RTKs?
Excess ligand or ligand independent activation occurs. Small molecule inhibitors bind where ATP would preventing activation.
What happens in normal oxygen levels compared to hypoxia?
Normoxia: OH and VHL bind to HIF1 alpha leading to proteosomal degradation. Hypoxia: ARNT binds to HIF1 alpha and transcription continues.
What is the success with targeting HIF and hypoxia?
Not very successful. Hard to target. Moderate outcomes of phase II and III clinical trials.
What are the limitations of HIF-1 inhibitors for cancer therapy?
Mechanism of action of inhibitor of HIF1. Need inhibitory agents to target HIF-1 and hypoxia without affecting healthy tissue associated with tumour. No side effect is the key limitation in the treatment of tumour hypoxia. HIF plays key role in resistance to cancer treatment.
What are two examples of small molecule probes for the hypoxia inducible factor prolyl hydroxylases?
PDH1-3 Fe(II) signals for HIF-alpha degradation via proteosomal machinery. FIH Fe(II) blocks binding of HIF to transcriptional coactivators.
What are the limitations of small molecule inhibitors in cancer therapy?
Side effects- bind to multiple targets (cell surface receptors and intracellular proteins) leads to high risk of toxicity. Adverse effects have been reported. Most inhibitors have a short life span. Development of resistance to these drugs is another major drawback.
