Initial Proof-of-Concept

Based on earlier work, it was clear that the ubiquitin-proteasome system could be successfully manipulated to promote the degradation of proteins that are normally stable in the cell. In 2001, Crews and co-workers first detailed the development of PROteolysis TArgeting Chimeric molecules (PROTACs), a method that provides the ability to induce degradation without biochemical manipulation. In order for this method to work, however, it would be necessary to identify ligands for both the E3 ubiquitin ligase and the protein of interest. 

Initial experiments showed by western blot that PROTAC-1 was, in fact, interacting specifically with the purified target protein MetAP2. Further in vitro experiments verified that PROTAC-1 can simultaneously bind to MetAP2 and recruit the remaining components of the complex. Having con- 

These initial experiments were crucial in the development of the PROTAC technique, investigating each individual interaction in the three component E3 ligase-P ROT AC-Target protein complex. In order for the PROTAC 

2 Targeting Tumor-relevant Proteins In vitro and In vivo 

The identification of ligands for targeting the AR and the ER was simplified due to the existence of natural high-affinity non-covalent ligands for both 

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In our own laboratories, initial proof-of-concept experiments established the utility of subcomponent self-assembly based upon copper(I) coordination and imine bond formation, most usefully in aqueous solution [24]. We have subsequently developed our research program along three main lines, seeking responses to a series of questions. 

A potent SARM, S-4 (15), was identified which demonstrated rapid and complete oral absorption at low doses and reasonable elimination half-life (t1/2 = 2.6-5.3 h) in rats, suggesting compounds such as this would be excellent candidates for clinical development [88]. These successes focused our efforts on the diaryl propionanilide class of SARMs of which many have been published [89-92], Recent studies demonstrated that these SARMs improve skeletal (soleus) muscle strength, increase lean body mass (LBM), reduce body fat, prevent bone loss in rats, in addition to promising pharmacologic activity in animal models of benign prostatic hypertrophy and male fertility [92-95], Ostarine is the most advanced SARM clinical candidate and has demonstrated exciting data from its initial proof-of-concept phase II clinical trial. GTx reported in December 2006 the results of this clinical trial which was... 

Despite their high affinity, these peptide-based compounds were not useful for cellular studies, primarily due to their poor cell permeability. To enhance their permeability, compounds were tethered to carrier peptides, which resulted in compounds that activated p53 function in cells at concentrations of 100-500 pM. Although such weak cellular activity clearly makes them unsuitable as potential therapeutic agents, they nevertheless provided the initial proof-of-concept that blocking the interaction between MDM2 and p53 can indeed be an effective means of activating p53. 

FDA is flexible in product testing for niAbs in early-stage feasibility cHnical trials intended to treat life-threatening conditions [5]. Feasibility clinical trials are pilot studies designed to provide an early characterization of safety and an initial proof of concept in specific patient populations. An immediately life-threatening condition is defined in 21 CFR 312.34 as a stage of disease in which there is a reasonable likelihood that death will occur in a matter of months or in which premature death is likely without early treatment. ... 

As a drug candidate progresses through the development stages after the initial proof-of-concept and phase I studies in humans, a reverse funnel of increasing patient exposure to the drug becomes evident (Fig. 2B). 

CE-SELEX has been used successfully to isolate aptamers for a variety of targets (see Table 28.1). While these initial proofs of concept experiments are promising, a more detailed study of the selection process is now needed. CE-SELEX has made the selection process dramatically faster. This will allow fundamental experiments assessing the effect of variables such as library concentration, target concentration, and incubation time to be performed for the first time. The 4-6 weeks that are necessary to complete a conventional selection have made these experiments unfeasible until now. 

X 10 cm This study provided initial proof of concept for the use of liquid crystalline matrices as on-demand stimuli-responsive systems for hydrophilic drugs. 

The initial proof-of-concept hybrid system had the reduced size of 1/300 energy of the full size system and 1/72 power compared to the full size system, discussed above and consisted of the 2 Ah, 32 V prototype lithium-ion battery and two ultracapacitors (52 F, 16 V) connected in series. The testing results presented in the following section refer to the reduced size hybrid systan. 

An initial proof-of-concept pilot study design was proposed on the basis of the data requirements presented in Figure 13.4. The methods to be used in the proposed pilot study were extracted from the error tolerance framework (see Figure 13.3) and a brief review of the methods available for studying driver behaviour and collecting error-related data. The proposed pilot study methodology is presented in Figure 13.5. 

For our initial proof-of-concept project, we prepared and used a pentablock copolymer poly[(2-cinnamoyloxyethyl methacrylate)-rfl -(2-trifluoroacetoxyethyl methacrylate)]-Wock-poly(solketal methacrylate)-Wock-poly(tert-butyl acrylate)-f>tock-poly(solketal methacrylate)-Wock-poly[(2-cinnamoyloxyethyl methacryIate)-rfl -(2-trifluoroacetoxyethyl methacrylate)], abbreviated as P(CEMA-r-TFAEMA)-fe-PSMA-fe-PtBA-f>-PSMA-f7-P(CEMA-r-TFAEMA) and shown in Figure 24.10. 

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