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Note: First targeted protein degrader hits the clinic (doi: 10.1038/d41573-019-00043-6 ) Protein degrader -- novel approach to kill cancer;   Design the new molecule which can link between E3-ligase + targeted molecule --> targeted molecule undergoes proteasomal degradation (ubiquitinylation)   alternative approaches besides the degrader; 1. small molecule interfering on protein stability (fold-unfold equilibrium) 2. target the upstream factors controlling protein stability/abundance 3. disrupting the protein-protein interaction and multi-target complexes 4. targeting deubiquitination process -- maintain the degradation on the particular target   Targeted degrader idea -- patent 1999   Degrader structure (bifunctional small molecule): 1. target-binding warhead 2. linker 3. E3 ligase recruiter   Basic drug properties; 1. bioavailable (amount in blood circulation) 2. selective 3. effective (disease relies on this ta...

Note: COSMIC-3D provides structural perspectives on cancer genetics for drug discovery (doi: 10.1038/s41588-018-0214-9) • COSMIC-3D is designed to enable greater understanding of the functional impact of mutations, generate new hypotheses on which mutations are cancer drivers and provide new opportunities for addressing these mutations pharmaceutically. • genetics, structural proteomics and drug development can be best described as ‘mutation-guided drug design’. • there remains much scope for expansion of the repertoire of precision therapeutic drugs targeting these mutations. • Both cancer genomic and protein structural data sources are individually great assets for scientists working in the field of oncology drug discovery. • COSMIC-3D currently maps cancer variant data for nearly 9,300 genes to nearly 37,000 protein structures, covering 390 key genes from the Cancer Gene Census. • The structure viewer displays the protein structure and small-molecule ligands, ...

Note: Small-Molecule Inhibitors Targeting DNA Repair and DNA Repair Deficiency in Research and Cancer Therapy (doi: 10.1016/j.chembiol.2017.08.027) Process that maintain genome integrity in normal cells - it will help cancer to develop resistance to radiation and DNA-damaging chemotherapeutics. New target; RAD51 recombinase, RAD52, and MRE11 nuclease, WRN DNA helicase. Synthetic lethality - two individual mutations but when combined  resulting in lethal phenotype. Hartwell, is the first guy who initiated the synthetic lethality with the cancer baring the DNA-repair proteins defect. Also, cancer that addict to particular DNA repair mechanism. Therefore, the target for synthetic lethality is that finding the protein that the cancer cell relied on for viability (but less important in normal cell) and inhibit theirs function. Synthetic lethality; two types 1.between-pathway (each backup for each other) 2.In-pw synthetic lethality, mutation either way of revers...