In vivo proof of concept

Inhibition of IGF-IR autophosphorylation by NVP-ADW742 results in a plethora of pro-apoptotic molecular events that may account for its effectiveness as a single agent and in enhancing the antitumor activity of a broad spectrum of chemotherapeutic and anticancer targeted agents. Initial in vivo proof-of-concept of the potential therapeutic benefit of blocking IGF-IR kinase activity in tumor cells was obtained in an orthotopic multiple myeloma (MM) model of bone and bone marrow disease. In this mice model, MM... 

I think Renu is right. Here, I review the growing body of in vivo proof-of-concept reports demonstrating the diazeniumdiolates efficacy in relevant animal models for treating a variety of clinical disorders. These reports have convinced me that within this chemistry lurks a vast opportunity for designing solutions to a host of biomedical problems. 

N-myristoylalendronic acid prodrug in vivo proof-of-concept... 

With such an in vivo proof of concept established, we profiled several of the CatA inhibitors in advanced models of cardiovascular diseases. These studies indicated a significant impact of CatA inhibition on several disease parameters including cardiac hypertrophy [2], Based on the outcome of these studies and its promising ADME and safety profile, one of our CatA inhibitors has now been progressed into phase I clinical trials. 

MDM2/MDMX antagonist stapled peptide ATSP-7041 vide infra) provides an in-depth and rigorous in vitro and in vivo proof-of-concept for drug development of this promising class of macrocyclic a-helical peptide therapeutics. 

An increasing number of studies have described the identification of stapled peptides for intracellular targets that exhibit potent target binding, in vitro efficacy and, in some cases, in vivo proof-of-concept (see ref. 19-24, 28, and 29 for reviews). The spectrum of such intracellular a-helical protein-protein interaction target space includes the BH3 Bcl-2... 

With proof of concept established that viral vector-delivered GAA can restore biochemical and histological phenotype of affected cells and cross-correct untransduced cells, these studies were quickly followed by in vivo assessment of Ad-mediated GAA delivery in animals. Intracardiac and intramuscular delivery of Ad-human GAA (hGAA) was performed in newborn rats by Pauly et al. (1998) resulting in 10- and 6-fold normal levels of GAA... 

As a proof of concept these recombinant food allergens can be used for in vitro diagnosis as well as for in vivo diagnostic approaches. Once, their equivalence to the respective natural counterpart is established, these proteins are available in unlimited quantity and can be produced in standardized quality. This offers a great improvement in setting up reliable diagnostic tools as well as allergen detection assays. 

In this case study a simulation strategy, based on a mechanistic PK/PD model, was developed to predict the outcome of the first time in man (FTIM) and proof of concept (POC) study of a new erythropoietin receptor agonist (ERA). A description of the erythropoiesis model, along with the procedures to scale the pharmacokinetics and pharmacodynamics based on preclinical in vivo and in vitro information is presented. The Phase I study design is described and finally the model-based predictions are shown and discussed. 

Proof of concept—in vivo In accordance with Study protocol... 

For brevity, only the pivotal toxicology studies are given. Examples of studies not included are proof-of-concept, comparability, toxicokinetic, pharmacokinetic, pharmacodynamic, local tolerance, and miscellaneous in vitro and in vivo studies. Pharmacokinetic and pharmacodynamic experiments generally used the pivotal toxicology animal model(s) because of the species specificity of the biopharmaceutical. 

Of course, unities are themselves labile at neutral pH, and therefore in principle one should be able to obtain an identical result by simply mixing salicylaldehyde, amines, and zinc in buffer in the presence of DNA. In a second report in 1999, we examined exactly this possibility [6]. Once again as expected, the pyrrolidine was the amine most retained by the DNA resin in the presence of salicylaldehyde and zinc. An inherent complication of this strategy, however, is that the labile library constituents made analysis and understanding of the results of library selection difficult. Furthermore, while useful as a proof of concept study, there is no clear pathway from the metal complexes identified in these studies to compounds suitable for use in structural studies or in vivo. As we will discuss later, consideration of such issues has been an important aspect of the design of more recent libraries targeting RNA recognition. 

Stauffer SR. Small molecule inhibition of the Bcl-X(L)-BH3 protein-protein interaction proof-of-concept of an in vivo chemopotentiator ABT-737. Curr. Top. Med. Chem. 2007 7 961-965. 

Lelirman G, Hogue IB, Palmer S, Jeimings C, Spina CA, Wiegand A, Landay AL, Coombs RW, Richman DD, Mellors JW, Coffin JM, Bosch RJ, Margolis DM (2005) Depledon of latent HIV-1 infec-don in vivo A proof-of-concept study. Lancet 366 549—555. 

Yeast display has come a long way since proof of concept in 1993 to the successful expression of a human cDNA library in 2005 and the demonstration that small-molecule-binding proteins can be isolated in 2007. Considering the rapid progress over the last two years and the inherent advantages over in vitro and other in vivo methods, it is clear that yeast display will soon overcome the current limitations and possibly become the method of choice for isolation of natural product-binding proteins. 

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