1. Innovative Gold/Platinum Anticancer Medicines and Theranostics
The clinical success of cis-platin has led to tremendous advances in metal coordination compounds for anti-cancer applications. In particular, planar coordination geometry and coordination unsaturation of d8 and d10 metal ions render their metal complexes to be unique scaffolds for the design of new diagnosis and therapy for treatment of cancers. We have employed ligands with N donor atoms such as porphyrins and C donor atom(s) such as N-heterocyclic carbenes (NHC) to construct cationic gold(III), Au(I), Pd(II), Pt(II) and Ir(III) complexes with good stability and cell permeability under physiological conditions. NHC ligands are able to stabilize metal ions against demetallation and render the metal complexes to be strongly emissive in solutions through suppression of excited state structural distortion. The rich luminescent properties of metal-N-heterocyclic carbene complexes are convenient spectroscopic handles for tracking of the complexes inside the cells and can also be used for the detection of biomolecular structures of relevance to cancers such as mismatched DNA. Some of these complexes exhibit potent cytotoxicity toward cancer cells and in vivo anti-tumor activities in multiple mice models of cancer including the cis-platin resistant and the metastatic ones. The in vivo metabolism of some of the anti-cancer metal complexes has been elucidated. Chemical formulation strategies of bioconjugation and encapsulation were used to deliver the cytotoxic anti-cancer metal complexes to the tumors with an objective to lower the toxic side effects. We have also applied click chemistry and photo-affinity probes, cellular thermal-shift proteomics and transcriptomic profiling to demonstrate that the anti-cancer metal complexes engage a number of molecular targets related to cancer progression and metastasis. Recently, we uncovered that for some gold(III) porphyrin scaffolds, the periphery of the porphyrin ligands can be activated by electrophilic gold center to selectively form covalent adducts with protein thiols. This is a new mode of biomolecular interaction that can be exploited for anti-cancer applications.
The clinical success of cis-platin has led to tremendous advances in metal coordination compounds for anti-cancer applications. In particular, planar coordination geometry and coordination unsaturation of d8 and d10 metal ions render their metal complexes to be unique scaffolds for the design of new diagnosis and therapy for treatment of cancers. We have employed ligands with N donor atoms such as porphyrins and C donor atom(s) such as N-heterocyclic carbenes (NHC) to construct cationic gold(III), Au(I), Pd(II), Pt(II) and Ir(III) complexes with good stability and cell permeability under physiological conditions. NHC ligands are able to stabilize metal ions against demetallation and render the metal complexes to be strongly emissive in solutions through suppression of excited state structural distortion. The rich luminescent properties of metal-N-heterocyclic carbene complexes are convenient spectroscopic handles for tracking of the complexes inside the cells and can also be used for the detection of biomolecular structures of relevance to cancers such as mismatched DNA. Some of these complexes exhibit potent cytotoxicity toward cancer cells and in vivo anti-tumor activities in multiple mice models of cancer including the cis-platin resistant and the metastatic ones. The in vivo metabolism of some of the anti-cancer metal complexes has been elucidated. Chemical formulation strategies of bioconjugation and encapsulation were used to deliver the cytotoxic anti-cancer metal complexes to the tumors with an objective to lower the toxic side effects. We have also applied click chemistry and photo-affinity probes, cellular thermal-shift proteomics and transcriptomic profiling to demonstrate that the anti-cancer metal complexes engage a number of molecular targets related to cancer progression and metastasis. Recently, we uncovered that for some gold(III) porphyrin scaffolds, the periphery of the porphyrin ligands can be activated by electrophilic gold center to selectively form covalent adducts with protein thiols. This is a new mode of biomolecular interaction that can be exploited for anti-cancer applications.
2. Proteomics and Drug Targets Identification
The identification of molecular targets of the bioactive compounds is crucial for realizing therapeutic applications. Our drug discovery program has established technology platforms employing transcriptiomics (next generation sequencing), proteomics (high throughput biological mass spectrometry), and bioinformatics (connectivity mapping, key-node analysis) in the elucidation of mechanisms of action of anticancer-active, metal compounds and natural products. Furthermore, we develop chemical probes (photoaffinity labeling, click chemistry, fluorescent compounds) for various bioactive compounds to identify the direct molecular targets. The target engagement of anti-cancer drugs in intact cells can also be investigated using probe-free methods such as those based on ligand-induced thermal stabilization of target proteins which, upon binding with the ligands, become more stable against heat-induced unfolding or precipitation even under cellular conditions. In combination with MS-based multiplexed quantitative proteomics analysis of the soluble proteins after thermal denaturation, the proteins engaged by the compounds of interest can be profiled in terms of the shift in the melting temperatures. Using these approaches, we have identified the molecular targets of a number of anti-cancer metal compounds and natural products with the drug-target interactions and downstream cellular mechanisms of action elucidated.
The identification of molecular targets of the bioactive compounds is crucial for realizing therapeutic applications. Our drug discovery program has established technology platforms employing transcriptiomics (next generation sequencing), proteomics (high throughput biological mass spectrometry), and bioinformatics (connectivity mapping, key-node analysis) in the elucidation of mechanisms of action of anticancer-active, metal compounds and natural products. Furthermore, we develop chemical probes (photoaffinity labeling, click chemistry, fluorescent compounds) for various bioactive compounds to identify the direct molecular targets. The target engagement of anti-cancer drugs in intact cells can also be investigated using probe-free methods such as those based on ligand-induced thermal stabilization of target proteins which, upon binding with the ligands, become more stable against heat-induced unfolding or precipitation even under cellular conditions. In combination with MS-based multiplexed quantitative proteomics analysis of the soluble proteins after thermal denaturation, the proteins engaged by the compounds of interest can be profiled in terms of the shift in the melting temperatures. Using these approaches, we have identified the molecular targets of a number of anti-cancer metal compounds and natural products with the drug-target interactions and downstream cellular mechanisms of action elucidated.
3. Natural Products from Chinese Medicines
Natural products, including those from Traditional Chinese medicines (TCM), are a significant source of lead compounds for drug discovery. Built on the foundation of R&D projects of drug discovery, we have identified a number of bioactive lead compounds from Chinese medicines with potential for treatment of cancer, neurodegenerative diseases and osteoporosis. Many of these lead compounds are also representative ingredients in the herbs found in prescribed formulae of Chinese medicine, whereas some were newly found to exhibit anticancer properties in pilot studies. Currently, we are developing several novel compounds showing in vivo inhibitory activities against mice cancer xenograft, and they will be further chemically modified and formulated to enhance the anticancer properties. Besides, purified compounds from Chinese medicines, Chinese Medicinal Formulations of mixed herbs (Fu Fang) are also investigated with an interest to apply phytochemical analysis and system biology for understanding the therapeutic properties. We are interested in co-develop Fu Fang which have been prescribed to cancer patients with good cure rate and safety in collaboration with the stakeholder company of the formulation. A multi-omics analysis is underway to decipher complex nature of therapeutic actions of the Fu Fang as well as to provide chemical fingerprint and biological response signature for quality analysis.
Natural products, including those from Traditional Chinese medicines (TCM), are a significant source of lead compounds for drug discovery. Built on the foundation of R&D projects of drug discovery, we have identified a number of bioactive lead compounds from Chinese medicines with potential for treatment of cancer, neurodegenerative diseases and osteoporosis. Many of these lead compounds are also representative ingredients in the herbs found in prescribed formulae of Chinese medicine, whereas some were newly found to exhibit anticancer properties in pilot studies. Currently, we are developing several novel compounds showing in vivo inhibitory activities against mice cancer xenograft, and they will be further chemically modified and formulated to enhance the anticancer properties. Besides, purified compounds from Chinese medicines, Chinese Medicinal Formulations of mixed herbs (Fu Fang) are also investigated with an interest to apply phytochemical analysis and system biology for understanding the therapeutic properties. We are interested in co-develop Fu Fang which have been prescribed to cancer patients with good cure rate and safety in collaboration with the stakeholder company of the formulation. A multi-omics analysis is underway to decipher complex nature of therapeutic actions of the Fu Fang as well as to provide chemical fingerprint and biological response signature for quality analysis.
Copyright © 2024 Chi-Ming Che