Approved drug | EPFL Graph Search

An approved drug is a medicinal preparation that has been validated for a therapeutic use by a ruling authority of a government. This process is usually specific by country, unless specified otherwise. In the United States, the FDA approves drugs. Before a drug can be prescribed, it must undergo the FDA's approval process. While a drug can feasibly be used off-label (for non-approved indications), it still is required to be approved for a specific disease or medical condition. Drug companies seeking to sell a drug in the United States must first test it. The company then sends the Food and Drug Administration's Center for Drug Evaluation and Research (CDER) evidence from these tests to prove the drug is safe and effective for its intended use. A fee is required to make such FDA submission. For financial year 2020, this fee was: for an application requiring clinical data (

2,942,965) and for an application not requiring clinical data (

1,471,483). A team of CDER physicians, statisticians, chemists, pharmacologists, and other scientists reviews the company's data and proposed labeling. If this independent and unbiased review establishes that a drug's health benefits outweigh its known risks, the drug is approved for sale. The center doesn't actually test drugs itself, although it does conduct limited research in the areas of drug quality, safety, and effectiveness standards. As of the end of 2013, the FDA and its predecessors had approved 1,452 drugs, though not all are still available, and some have been withdrawn for safety reasons. Accounting for subsequent corporate acquisitions, these approvals were earned by approximately 100 different organizations. In the European Union, it is the European Medicines Agency (EMA) that evaluates medicinal products. In Japan, the agency regulating medicinal products is Pharmaceuticals and Medical Devices Agency (PMDA). On average, only one in every 5,000 compounds that makes it through lead development to the stage of preclinical development becomes an approved drug.

Targeting the oncogenic signaling of the transcription factor STAT3 with potent and selective monobody inhibitors

Grégory La Sala

Many targeted cancer therapies fail to improve the overall survival of patients. Limitations involve low drug selectivity and the rapid development of resistance. Moreover, the majority of oncogenic drivers presently remain considered as undruggable as these proteins often lack well-defined binding pockets able to fit small molecular antagonists. The need for novel strategies to expand the number of druggable targets thus appears crucial. STAT3 is a transcription factor that is constitutively active in a majority of solid and hematological tumors. It is considered a central target for cancer therapies, as it induces the transcription of genes essential for tumor proliferation, including anti-apoptotic genes, cell cycle regulators and angiogenic factors. Therefore, the inhibition of STAT3 represents a promising therapeutic strategy. However, the targeting of STAT3 still remains a formidable challenge due to the sparse number of chemical probes able to bind to non-enzymes. The engineering of protein binders could overcome many of the challenges in developing STAT3 antagonists. While most common approaches to preclude STAT3 activation consist in either inhibiting its phosphorylation by upstream tyrosine kinases with clinically-approved drugs, or in preventing the SH2 domain-dependent STAT3 dimerization using pre-clinical small molecule probes, the targeting of other STAT3 domains, such as its Coiled-coil or N-terminal domains, has not been thoroughly investigated. Our lab uses small engineered antibody mimics derived from a fibronectin type 3 scaffold (termed monobodies) capable of high affinity and selective binding. In addition, their small size (~10 kDa) and lack of disulfide bonds makes them promising candidates for intracellular antagonistic use. In this work, we selected several monobodies using phage and yeast display that bind to previously untargeted domains of STAT3 with low nanomolar affinities. The monobodies MS3-6 and MS3-N3, binding to the Coiled-coil and N-terminal domain of STAT3 respectively, showed high selectivity to STAT3 as compared to other STAT family members and other unrelated proteins. Additionally, the monobodies strongly inhibited the transcriptional activity of STAT3 in luciferase reporter assays, reduced mRNA levels of STAT3 downstream genes in human lung cancer cells, decreased STAT3 phosphorylation levels upon IL-22 stimulation and interfered with STAT3 nuclear translocation. Notably, the precise blockade of these previously untargeted key domains using monobodies provide new insights into the STAT3 signaling and expand the current strategies to preclude its activity. Altogether, we have developed the first selective monobody inhibitors against a transcription factor implicated in cancer and inflammatory diseases, and used them as biochemical tools to further characterize a poorly understood alternative IL-22R signaling axis involved in STAT3-driven human disorders such as colitis and psoriasis.

EPFL2020

Targeting the oncogenic signaling of the transcription factor STAT3 with potent and selective monobody inhibitors

Grégory La Sala

EPFL2020