Gabriela Chiosis: Drug Discovery and Development /Translational Research

Another major focus of my laboratory is to translate the mechanistic findings and the chemical biology tools into treatment strategies. These efforts encompass a large spectrum of activities such as lead compound discovery and development, medicinal chemistry, computational analyses, assay development, pharmacokinetic and pharmacodynamic studies, in vivo efficacy studies, biomarker discovery, diagnostic assay development, combination therapy studies, intellectual property development, and commercialization strategies.

Dr. Tony Taldone from my lab shares his thoughts on the challenges and rewards of drug discovery:

Drug discovery: Challenges of making a drug

Drug discovery is a long and difficult endeavor but can be extremely rewarding when such efforts lead to the clinical translation of important discoveries that can potentially benefit many. Such a process generally begins with the exciting discovery of a protein in a biological pathway that can potentially be modulated through the use of a small molecule. If structural information is available on the protein of interest, this can be used to guide structure based drug design (SBDD). In this approach, ligands are designed to fit within a binding pocket on the protein and computationally evaluated for maximal interaction with the protein. Selected compounds can then be chemically synthesized and evaluated in assays designed to measure the ability of the compound to bind. The information from these initial studies can be used to confirm binding and validate the computational design of ligands, which in turn can be used to design more potent analogs. In a complementary approach, the availability of biological assays can be used to screen large libraries of compounds referred to as high-throughput screening (HTS). Such screens can result in interesting “hits”, which may serve as useful probes for further biological investigations, however, they rarely have the desired properties suitable for a drug. Whether “hits” are obtained by SBDD, HTS or by other means, it is rare that these are suitable as a drug and require extensive optimization into potent lead molecules and further into clinical candidates. These efforts are typically extremely challenging and expensive. Hits obtained from initial screens do not have the potency nor the ideal pharmacokinetic (PK) properties to be suitable as drugs. These “hits” have to be chemically modified through the synthesis of numerous analogs that improve potency while at the same time consider the potential PK effects. Therefore, a parallel approach in analog development that considers both potency and PK properties is the current paradigm in drug discovery that offers the best chance for the successful development of a drug.

Drug discovery is a very expensive process and it is estimated that it costs approximately $800 million to successfully bring an anti-cancer drug into market. Therefore, the stakes are very high and failures or even setbacks can have serious consequences for the economic well being of any organization involved in drug discovery. While it used to be the case that most drugs in clinical trials would fail as a result of poor absorption, distribution, metabolism and excretion (ADME) properties, now the primary reasons for drug failure is a lack of efficacy and/or unacceptable toxicity. This change has occurred as a result of a greater appreciation of the importance of ADME through the implementation of numerous assays which have greatly improved our ability to predict PK in humans.

Early screening for ADME properties has become the norm in the pharmaceutical industry. The investigation of ADME and a good understanding of the physicochemical properties (solubility, stability, etc.) of candidates as well as potential toxicity issues early in the drug discovery process can result in substantial savings in both money and time. The results from these early studies can guide in making crucial go or no-go decisions. Early ADMET studies eliminates wasted development effort on unsuitable compounds and can shift medicinal chemistry efforts towards more promising areas of development.

Drug discovery will always be a risky business, however, these risks as well as the time involved can be minimized if the liabilities of a molecule are known and adequately addressed early in the process. As a scientist, I can think of no more satisfying achievement that the translation of discoveries made at the bench into useful therapeutics for the treatment of disease.