p38, JNK and ERK are key important elements that modulate different cellular activities including response to infection and/or pro-inflammatory stimuli.
p38 MAP Kinase has been subject to many drug discovery and development programs due to its direct implication in many inflammatory diseases. The first generation of ATP-site competitive inhibitors failed in clinical trials due to its poor effectiveness while the first attempt on a second generation of partially-allosteric compound such as BIRB-796 or PF-03715455 failed in clinical trials due to its liver toxicity or poor pharmacokinetics properties. Molecular insights for both failures show that ATP-site competitive inhibitors (type I) or partially competitive (type II) exhort a pro-inflammatory signal in infiltrated cells and/or a compensation mechanism that overcomes pharmaceutical inhibition. A possible solution for this hassle is the discovery of a third generation of p38 inhibitors that modulate kinase activity in a distant region form the active site, the so called type IV inhibitors.
JNK MAP Kinases are key signals in the brain for both neuronal apoptosis and amylogenic processing of APP. These are the two most important characteristics in Alzheimer's disease. In fact, sound scientific experimentation has validated JNK as an Alzheimer's disease target-Allinky's founders are co-authors in some of these articles.
Taking into account these promising findings, Allinky started in 2009 a drug discovery program on allosteric inhibition of JNK and p38 aiming at modulating enzyme activity. The program has lead to the discovery of three novel chemical structures that bind to different allosteric sites including a protein-protein interaction site. All three compounds modulate JNK and p38 activity at nM concentration.
Ras protein belong to a class of proteins called small GTPase and are involved in cellular signal transduction including cell growth and division. The over activation of Ras signaling can lead to uncontrolled cell growth and ultimately to cancer. Either the inappropriate activation of the gene or the constitutively active mutated-Ras protein has been shown to play a key role in signal transduction, proliferation and malignant transformation. Indeed, Ras is the most common oncogene in human cancer, over expression or mutations that permanently activate Ras are found in one out of forth of all human tumors and up to 90% in certain types of cancer such as pancreatic cancer. Since the targeting of Ras family proteins at its active site (GTP pocket) has poor selectivity, the pharmaceutical industry concentrated the efforts on farnesyltransferase inhibitors (FTIs) - a class of cancer drugs that target protein farnesyltransferase with the downstream effect of preventing the proper functioning of Ras. However, these experimental drugs have reported intolerable side effects. In order to effectively and selectively target Ras proteins, Allinky is developing allosteric Ras inhibitors based on its proprietary findings of allosteric binding sites within Ras protein family. The first generation of this novel class of drugs has an IC50 of 100nM and compounds are currently under lead optimization phase.
Alzheimer’s disease. Allinky is involved in a drug discovery program to target neuroinflammation-related proteins that play a critical role in the onset and progression of Alzheimer’s diseases. State-of-the-art science has shown that IPS-derived neurons from Alzheimer’s disease patients present several interesting features related to Alzheimer’s disease but these features are not sufficient to explain disease onset and progression. Moreover, science has shown that non-neuronal cells in the brain such as astrocytes and microglia driving response to inflammatory stimuli might contribute significantly to Alzheimer’s disease. This contribution is in the form of: i) misprocessing of APP; ii) resistance to neuron progression signals such as IGF-1; and iii) over expression of certain kinases behind neuronal dead. Following this new approach Allinky is involved in the discovery of new small molecules targeting neuroinflammation and thus useful for the treatment of the Alzheimer’s disease.
Cardiovascular Disease. Allinky plans to be involved in a new drug discovery program for the treatment of different cardiovascular diseases such as aneurism, stenosis and atherosclerosis. All these indications have in common an over expression of chronic vascular remodeling cell signals leading to disease progression. Novel targets have been validated in animal models to begin with in silico drug design and crystallization studies in the future to come.