Epichem and Sanoosa team up against RAS-related Tumors
Evaluation and early-stage optimization of a promising novel compound series targeting the oncogenic RAS signaling pathway.
RAS (KRAS, NRAS and HRAS) is the most frequently mutated gene family in cancers, and investigators have sought an effective RAS inhibitor for more than three decades. RAS is mutated in a way that causes loss of its GTPase activity, thereby activating downstream effectors of RAS pathways.
Novel, Small Molecule Therapeutic for Oncology
Epichem, Australia’s premiere contract medicinal chemistry company has partnered with Sanoosa, a computational drug discovery company to develop a novel hit series active and selective in a KRAS synthetic lethal phenotypic screening module.
A highly novel, small molecule series of inhibitors has been identified that selectively kills a suite of oncogene-expressing engineered cell lines. The sub-μM level of activity demonstrated by this unique hit series across K-Ras synthetic lethal cell-lines is very exciting given the novel, unoptimised nature of the chemical structure. The compound has a low molecular weight (FW 236) and in silico predicted physicochemical properties in the drug-like domain. The scaffold is amenable to modification for analogue production and a small compound library has been prepared.
Positive results expected in less than two years
The teams at Epichem and Sanoosa have demonstrated track records in innovative drug discovery, project management, collaborative research, and milestone attainment. Together, we have an exciting opportunity to enter a unique sphere of chemical space and develop valuable intellectual property (IP) in a highly competitive therapeutic area.
The initial active hit is supported by a set of closely related analogues that also demonstrate activity in vitro. The lead hit has been profiled in other phenotypic screens representative of several contemporary therapeutic areas of interest and did not demonstrate pan activation or inhibition. Consequently, the compounds are not anticipated to be promiscuous hits. The structure has huge potential as a drug-like scaffold which can be rapidly explored.
RAS-proteins as Oncology Targets
Mutations in Ras protein family members are found in approximately 30% of human cancers. K-Ras is the most frequently mutated Ras isoform, with mutations identified in 90% pancreatic, 45% colorectal and 35% of lung cancers. K-Ras mutations have been associated with an increased tumorigenicity and poor prognosis. Importantly, the inhibition of activated K-Ras has been shown to revert malignant cells to a non-malignant phenotype and cause tumour regression both in vitro and in vivo. Various compounds, most notably from Amgen, Mirati Therapeutics and Verastem, targeting RAS-induced cancers are currently in clinical trials with no real breakthrough yet in this field.
RAS proteins interact with several downstream effectors, primarily Raf protein kinases and phosphoinositide 3-kinases (PI3Ks). The RAF protein family has emerged as an extremely promising and validated target for protein-directed anticancer therapies. The Raf > MEK > ERK signaling axis is essential for oncogenesis and hence, elimination of Raf function is predicted to be an effective treatment for the many cancers initiating with EGFR
and Ras lesions.
The activity demonstrated in a suite K-Ras synthetic lethal cell-lines by the novel compounds described in this proposal presents a very exciting opportunity to enter this targeted area of anticancer therapeutics.
Research and Development Stage
This opportunity is at the earliest phase of development with a huge potential for rapid advancement. A partner with multiple screening capabilities could capitalise on the discovery and profile this unique series across a panel of targets.
The partnership between Epichem and Sanoosa provides an outcome focused approach to project progression, drawing on extensive professional experience in the efficient development and delivery of drug-like molecules, knowledge of the drug discovery process and interaction with collaborative organisations.
Epichem (https://epichem.com.au) is a wholly owned subsidiary of the ASX listed company PharmAust Limited. Located in Technology Park, Western Australia, Epichem has been delivering products and services in synthetic and medicinal chemistry to the global drug discovery and pharmaceutical industries in over 40 countries worldwide for over 17 years. Epichem has newly constructed purpose-built, state-of-the-art laboratories and has world class equipment and expertise in synthetic and medicinal chemistry to support drug discovery projects, and for the cost-effective synthesis of drug analogue libraries and intermediates. It also has a rapidly growing catalogue of pharmaceutical reference standards.
Epichem is the winner of the WA Industry Export Award 2019 for International Health, the 2020 Inspiring Story of Celebrating Remarkable Resilience Nomination for WA for the Australian Export and Investment Awards and the 2020 GHP Biotechnology Award winner for Most Innovative Chemistry Service Provider – Australia and Best in Organic Chemistry Solutions 2020. Epichem generated Aus$3.5M in revenues in the 2020 FY. For more information, visit www.epichem.com.au
Sanoosa is a computational drug discovery company based in Melbourne, Australia. Sanoosa's proprietary developed small molecule drug discovery & design platform utilises its forecast-software to replace most of wet chemistry and achieves >20-fold productivity gains in early drug discovery compared to conventional methods. Sanoosa’s technology comprises an agile process and is focused on difficult to drug disease targets, like protein-protein interactions.The AI and ML components of Sanoosa’s technology achieve a high degree of selectivity for novel compounds and foster the automation of the discovery process.Most notably, the technology platform was successfully validated for its application to bind small molecules on RNA structures.The technology platform is target agnostic.
The application of Sanoosa’s technology and process bring novel drug candidates significantly earlier into human trials with significant implications on time to market. Sanoosa focuses primarily on debilitating chronic inflammatory diseases and underserved cancers (e.g. COPD, psoriasis, and its sub-diseases and pancreatic, ovarian cancers).