Priaxon AG, based in Munich, Germany, discovers and develops small molecule therapeutics for novel target-ligand interactions. Proprietary, highly versatile chemo-informatics tools rapidly identify essential molecular determinants of novel target-ligand interactions, and apply this information to select suitable ligand motifs in previously unexplored chemical space.
Our company goal is to demonstrate the superior efficiency in terms of innovation, timelines and R&D economics of applying Priaxon’s tools to the rapid evaluation and NCE based exploitation of new drug targets.
Combined, the Priaxplore® tools provide for rapid initial in silico hit prediction, reduced synthetic chemistry workload and focused hit screening campaigns of pre-optimised molecular entities with novel chemotypes. Moreover, the required input for successful application is either target structural information, or the structure of a known ligand, but not necessarily both.
Priaxons R&D approach is truly target-based, and applies similarly to novel drug targets (e.g. PPIs, epigenetic targets), and novel interaction mechanisms on established targets (e.g. allosteric control of kinase activity).
Unlike many competitors’ approaches, it is not restricted to technologies, chemical libraries or assay formats specific to a given target class. On the contrary, potential novel targets can be evaluated for their accessibility and biological impact using rapidly generated, proprietary tool compounds- as soon as structural information is available on either the target or a known modulator.
Proof of the attraction and validity of Priaxons R&D process is constituted by a 2010 early discovery collaboration/license deal with Boehringer Ingelheim on Priaxons NCE inhibitors of the mdm2/p53 interaction. An ongoing collaboration with GlaxoSmithKline (GSK) on an undisclosed ion channel PPI target of relevance in CV indications underscores continued Industry interest.
Company Technology: PriaXplore® increases innovation and efficiency in drug R&D
PriaXplore® is a technology suite that applies computational approaches, combined with complex synthetic chemistry to address thus far intractable molecular interactions of relevance in human health and disease with small molecule based therapies.
It is of note that Priaxplore® is not limited by company IP/USP on defined areas of chemical space (e.g. “macrocycle companies”), assay technology (e.g. target specific proprietary PPI assay companies) or manufacturing capabilities (linkers, staplers, etc), and thus provides maximal freedom in the selection of targets, chemotypes and assays.
At the outset of a given project, Priaxplore® in silico tools are employed to assess ligand interaction dynamics, and identify essential, optional and induced binding interactions between the partners of interest.
Based on this information, preliminary pharmacophores are constructed, and combined with information on the feasibility of chemical synthesis for the most suitable chemotypes identified, allow the in silico screening of relatively large areas of chemical space to identify chemical scaffolds likely to replicate the required target interactions. Additional detailed modelling to fine tune molecular interactions is then carried out on increasingly smaller subsets of structures of interest.
Importantly, initial searches in chemical space are entirely focused on selecting for appropriate molecular interaction motifs. This opens up a far wider range of chemotypes for later rational lead optimization than is found in typical drug-property pre-optimised classical libraries, and return novel scaffolds with very good IP/FTO situations. In addition, recent data shows that compounds emerging from this process are amenable to classical MedChem optimization for potency, selectivity and ADMET/DMPK parameters.
As a result, Priaxon can efficiently narrow down the number of compounds for actual chemical synthesis from several thousands of in silico hits to less than 100 predicted in vitro hits for testing and confirmation, typically in the space of less than 6 months between initiation of modelling and initial hit confirmation (Fig 2, Fig 3).
Based on experience with 20 separate viral, bacterial, plant protein and oncoprotein targets, hits have been generated for 75% of these, of which another 50% progressed to lead identification.
Hence, our business model builds on the rapid generation of high quality IND candidates against a range of novel targets, validating our technology with each successful project and providing a quantifiable valuation base as well as enforceable IP.
The company focus is on NCE development for novel oncology targets with preliminary clinical validation, and on developing anti-infective therapies for novel targets and/or with new modes of action circumventing known bacterial drug resistance mechanisms.
Company Pipeline: Focus on Oncology/Immunology and Infectious Disease
• Transcription Inhibitor: The molecular target of this project is a transcription factor required for the correct assembly of Pol II (RNAPII), which in cancer cells is implied in the provision of high levels of oncoproteins and anti-apoptotic factors for the maintenance of the transformed phenotype. The lead compound in this project is active at low dose in various PDX models and is undergoing further development towards IND
• Mcl-1: Inhibition of mcl-1 is associated with the restoration of tumour cell sensitivity to pro-apoptotic signals. Our lead compounds show high potency in vitro, and spare the closely related Bcl-Xl, implied in safety issues with current similar compounds. This project is currently being transitioned to in vivo testing stages.
• Bcl-6: Bcl-6 belongs to the BTB/POZ transcription factor family, and is very commonly overexpressed in diffuse large B-cell lymphomas (DLBCL). Inhibition of Bcl-6 was shown to inhibit proliferation of DLBL in vitro, indicating an excellent therapeutic approach for Bcl-6 positive DLBCL. Our compounds are currently undergoing in vitro and in vivo testing.
• BET modulators: Targeting epigenetic reading mechanisms is a relatively novel approach, but has the advantage of preliminary validation in preclinical and clinical settings. Bromodomain inhibitors are currently being investigated clinically in oncology and autoimmune/inflammatory settings. Using a target specific structure-based library design strategy Priaxons ultimate aim is the Priaxplore-based development of BET- specific inhibitors rather than pan-inhibitors
• HPgGT Inhibitor for the therapy of persistent /drug resistant H pylori infections. This project is being developed in conjunction with academic collaborators. Lead compounds show activity in proprietary in vitro models and are undergoing further optimization.
• PEX-14 Modulation of this target may result in novel therapies for trypanosomal infections in the developing world. This project is being developed in conjunction with academic collaborators and intended as a publishable show-case project to demonstrate the capabilities of the Priaxon approach. Biophysically verified Hit compounds show good biological activity and being developed towards the nomination of preclinical development candidates.
• FtsZ: This target is required for bacterial wall synthesis during cell division. Inhibition of FtsZ is a novel approach for the development of innovative antibiotics with the ability to overcome antibacterial resistance. Priaxon expect to obtain biological activity data by Q4 of 2014.