DUBLIN – Inthera Bioscience AG raised CHF10.5 million (US$10.8 million) in a series A round to further its development of small-molecule inhibitors of protein-protein interactions, one of the most important frontiers in drug discovery.
The Zurich, Switzerland-based company is employing a proprietary technology that enables it to approach the problem in a rational and repeatable manner, by translating the binding characteristics of the key helical peptide interface located in one of the proteins of interest into a small molecule based on an oligo-oxopiperazine backbone. An amino-acid side-chain is attached to that scaffold, and the resulting structure, dubbed an oxopiperazine helix mimetic (Ohm), has a molecular weight that is typically less than half that of the original peptide.
The technology comes from the lab of co-founder Paramjit Arora, professor of chemistry at New York University. He had originally pursued peptide-based approaches to modulating protein-protein interactions but later switched to small molecules because of their superior drug-like properties. “He found that oxopiperazines can be modularly assembled in a peptide-like fashion,” Inthera CEO and co-founder Ulrich Kessler told BioWorld Today. “The trick is really our backbone is smaller than the representative backbone.” Its lead program is focused on reactivating the p53 tumor suppressor pathway in human papillomavirus (HPV)-associated cancers. “We will nominate a preclinical candidate toward the end of the year,” Kessler said. All going well, the program should enter the clinic in 2019.
The approach is based on the interaction between two HPV oncoproteins, E6 and E7, and a transcriptional co-activator, p300, which is responsible for post-translational acetylation of p53. “We keep them away and let p300 do its job,” Kessler said. “In this way we reactivate the p53 pathway and enable cells to die when they should, when they have DNA damage.”
A second program is targeting solid tumors in which hypoxia-inducible factor 1 alpha (HIF-1 alpha) signaling is implicated. It is also based on interactions between p300 and HIF-1 alpha.
Last year’s approval of the B-cell lymphoma-2 (BCL-2) inhibitor Venclyxto (venetoclax) in chronic lymphocytic leukemia (CLL) validated – after an exhaustive effort – the idea that protein-protein interactions were amenable to drug development. Its developer Abbvie Inc., of North Chicago, spent around two decades on the problem. (See BioWorld Today, April 13, 2016.)
Protein-protein interactions, which regulate many fundamental biological processes within cells, tend to be intractable to classical drug discovery approaches. The targets involved typically do not offer medicinal chemists the kind of deep binding pockets they can readily find in traditional drug targets, such as receptors or enzymes. Larger molecules, such as proteins or peptides, can readily block such interactions, but they lack the cell penetration required to make them useful. Even modified peptides, such as stapled peptides, have proved challenging to develop, given their radically different PK profiles as compared with those of small molecules.
Several groups have adopted nuclear-magnetic-resonance-based drug fragment screening, which involves identifying several small-molecule fragments that can partially bind the target of interest. “Fragment-based approaches – Steve Fesik started all this – have been for many development projects notoriously frustrating,” Kessler said, referencing the pioneering work on venetoclax of the former Abbott Laboratories (now Abbvie) scientist, now at Vanderbilt University School of Medicine. Kras Therapeutics Inc. and the Genentech arm of Roche Holding AG have also pursued that approach in the hunt for Ras inhibitors, while Kevan Shokat at the University of California, San Francisco, has employed a technique called tethering to develop covalent inhibitors of a specific mutated form of KRAS. Inthera’s Arora has also published data on the inhibition of the interaction between Ras and Son of Sevenless (Sos).
Warp Drive Bio Inc., of Cambridge, Mass., has secured a large deal with Paris-based Sanofi SA on the back of its polyketide engineering approach to targeting Ras and other proteins. That involves hacking the natural interaction that occurs between polyketides such as rapamycin and an intracellular protein, FK506, with which it forms a complex. By synthetically varying the polyketide structure, the company is varying the resulting composite surface that arises during the complex formation – and that surface can therefore be programmed to disrupt protein-protein interactions of choice.
Inthera’s approach offers speed and reproducibility, Kessler said. The company has access to a large database of protein-protein interactions against which its technology could be deployed. It is open to pursuing technology-based deals with big pharma firms, as well as drug-based deals once its development programs mature.
Merck Ventures, which also led the Inthera’s €3.4 million (US$3.8 million) seed round in 2015, led the series A round. Other participants included Aglaia Biomedical Ventures, Novo Seeds and an unnamed private investor. Emmanuelle Coutanceau, of Novo Seeds, and Keno Gutierrez, of Merck Ventures, have both joined Inthera’s board.