Novel antisense oligonucleotide approach leads to the discovery of AZD4785 targeting KRAS messenger RNA
KRAS is a considered a prime target to develop personalised therapies for cancer due to the high levels of mutations found in this gene, across multiple tumour types. Until recently, this target has been classed as ‘undruggable’, following numerous failed attempts to discover effective therapies.
In the recent issue of Science Translational Medicine, scientists at AstraZeneca in our IMED Biotech Unit, in collaboration with our partners IONIS Pharmaceuticals have developed the first antisense oligonucleotide (ASO) that can inhibit KRAS.
KRAS is a small, membrane-bound protein that acts as a molecular switch to regulate cellular signalling and cell growth. By cycling between active GTP-bound and inactive GDP-bound state, KRAS controls the signalling cascade within the cell. In cancer, KRAS mutations occur most frequently in solid malignancies with the vast majority causing activation to ‘switched-on’ state. Due to this tight binding with GTP in the activated state, and lack of suitable binding pockets on the protein surface, discovery of effective therapeutics against this target has proved challenging.
Using proprietary antisense technology, IONIS scientists have developed a second generation ASO that targets a unique genetic sequence within the KRAS mRNA.
“It has been fantastic working at the forefront of antisense technology with IONIS. AZD4785 offers an exciting potential to overcome challenges faced in developing inhibitors of KRAS through traditional platforms.”, says Sarah Ross, Oncology Lead Biologist, IMED Biotech Unit.
“IONIS-KRAS-2.5Rx incorporates Ionis’ Generation 2.5 chemistry, which we developed to increase the potency of antisense drugs by increasing affinity for the target RNA. This advancement creates opportunities for drugs like IONIS-KRAS-2.5Rx to effectively target traditionally ‘undruggable’ targets, like KRAS, in tumours” said Brett Monia, senior vice president of drug discovery and franchise leader for oncology and rare diseases at Ionis Pharmaceuticals. “We are excited to work with AstraZeneca to bring IONIS-KRAS-2.5Rx to the clinic as the first anticancer drug targeting KRAS.”
Together, scientists from IMED and IONIS went on to demonstrate pre-clinically AZD4785 potently and selectively depletes cellular KRAS and inhibits KRAS dependent signalling and cell growth.
Sarah Ross added, “We used a selection of patient-derived xenograft models with KRAS gene mutations, and for the first time were able to directly show reduction in the growth a lung tumour as a result of a KRAS targeted molecule. This, together with data from other in vivo models helped us build a body of evidence to support progression to clinical first-time-in-man testing for AZD4785.”
The discovery of AZD4785 exemplifies the potential of combining antisense technology with AstraZeneca’s knowledge of tumour drivers and resistance. Through our collaboration with IONIS, we have discovered a new way of overcoming this challenging target in our quest to develop novel therapeutics for cancer.
ABOUT IONIS PHARMACEUTICALS, INC.
Ionis is the leading company in RNA-targeted drug discovery and development focused on developing drugs for patients who have the highest unmet medical needs, such as those patients with severe and rare diseases. Using its proprietary antisense technology, Ionis has created a large pipeline of first-in-class or best-in-class drugs, with over three dozen drugs in development. SPINRAZA® (nusinersen) is a drug that has been approved in the U.S. and EU for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients. Biogen is responsible for commercialization of SPINRAZA. Drugs that have successfully completed Phase 3 studies include volanesorsen, a drug Ionis is developing and plans to commercialize through its wholly owned subsidiary, Akcea Therapeutics, to treat patients with either familial chylomicronemia syndrome or familial partial lipodystrophy; and inotersen (IONIS-TTRRx), a drug Ionis is developing with GSK to treat patients with TTR amyloidosis. Both drugs are progressing toward regulatory filings in the second half of 2017. Ionis’ patents provide strong and extensive protection for its drugs and technology. Additional information about Ionis is available at www.ionispharma.com.
AstraZeneca is a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of cardiovascular, metabolic, respiratory, inflammation, autoimmune, oncology, infection and neuroscience diseases. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information please visit: www.astrazeneca.com.