Warp Drive Bio is developing a first-in-class SMART™ inhibitor of the activated form of mutant RAS (GTP-bound RASG12C). Although RAS is recognized as a key driver of multiple cancers, it is a target that has been undruggable due to the lack of a hydrophobic pocket on the RAS surface, which prevents high-affinity small molecule binding. Warp Drive Bio has deployed a differentiated and chemically diverse series of highly potent and selective SMART™ compounds to target RAS and block downstream RAS signaling, and thus drive tumor-specific cell death. Importantly, SMART™ enables targeting of the active, GTP-bound form of RAS, a nucleotide state that is responsible for driving tumorigenesis and for which no inhibitors currently exist. The long-term goal of the Warp Drive Bio RAS program is to provide more effective and durable treatment responses in the ~30% of cancer patients with
Key Facts About RAS*
*McArthur, G.A. Exploring the Pathway: The RAS/RAF/MEK/ERK Pathway Fact Sheet. American Society of Clinical Oncology. http://am.asco.org/exploring-pathway-rasrafmekerk-pathway-fact-sheet. Published May 31, 2015. Accessed April 6, 2016.
Warp Drive Bio is developing a series of SMART™ allosteric, kinome-selective ERK inhibitors. Activation of the RAS-RAF-MEK-ERK pathway via growth factor signaling or oncogenic mutations is a common feature across many cancers, and resistance to clinically-approved RAF and MEK drugs is often driven by reactivation of ERK. It has also been established that dynamic regulation of MAPK pathway signaling flux is critical for dictating the cellular consequences of ERK activation. Therefore, inhibition of ERK is expected to address clinical resistance to RAF/MEK inhibitors and demonstrate synergistic anti-tumor activity in combination with other targeted therapies. By targeting an allosteric site on ERK in a highly selective manner, Warp Drive Bio's SMART™ ERK inhibitors offer a differentiated mechanism for modulation of ERK activity to address cancers driven by hyperactive ERK signaling and to overcome treatment-induced resistance. Warp Drive Bio retains worldwide commercial rights to the ERK program.
Key Facts About ERK
1Dhillon et al., MAP Kinase Signaling Pathways in Cancer. Oncogene (2007)
2Ryan et al., Targeting RAS Mutant Cancers, Is ERK the Key?, Trends in Cancer (2015)
3Van Allen, et al., The Genetic Landscape of Clinical Resistance to RAF Inhibition in Metastatic Melanoma, Cancer Discovery (2014)
Novel antibiotics with new and differentiated mechanisms of action are urgently needed to combat the emerging global threat of multi drug-resistant bacterial pathogens. Warp Drive Bio is deploying its proprietary, Genome Mining™ Platform to discover entirely novel classes of antibiotics, which we refer to as “neomorph” antibiotics.
The Warp Drive Bio approach represents a paradigm shift, whereby drug discovery is initiated at the level of the microbial genome, allowing for the rapid discovery of novel antibiotics with differentiated mechanisms that may otherwise have been overlooked in more traditional, activity-based discovery efforts. Biosynthetic gene clusters that encode natural product antibiotics often include an embedded resistance gene expressed in tandem with the natural product to confer resistance to the bacterial host organism. By searching our high resolution genomics database for previously unexplored biosynthetic gene clusters that contain embedded resistance genes, Warp Drive Bio scientists are able to readily identify candidate antibiotic classes. The embedded resistance gene also often provides insight into the target of the encoded natural product;1 therefore, Warp Drive is also able to conduct mechanism-based searches for new classes of antibiotics at the genomic level.
Upon identification of novel biosynthetic gene clusters with embedded antibiotic resistance genes, Warp Drive Bio's suite of state-of-the art molecular biology and heterologeous expression technologies are applied to isolate and characterize the corresponding natural product, which serves as a novel chemical scaffold. Warp Drive Bio's integrated chemistry team then deploy proprietary biosyntheic enginerring tools (an approach we call 'Evolvalog') in addition to semi-synthetic and fully synthetic chemistry approaches developed through advancement of our natural product-based SMART™ platform to drive lead optimization and fuel development of new antibiotic drugs.
Warp Drive is evaluating over one hundred novel classes of potential natural antibiotics that were previously undiscovered and thus never analyzed for their impact on human health. There are currently ten classes of natural antibiotics that have been approved for patient use as compared to five classes of synthetic antibiotics. The last antibiotic from a novel natural class approved by the FDA was daptomycin, discovered more than 30 years ago.
Warp Drive is currently collaborating with Roche to advance multiple novel-scaffold, novel-mechanism antibiotics with the goal to treat multi drug-resistant Gram negative infections.
Key Facts About Antibiotic Resistance
1Alanjary et al., The Antibiotic Resistant Target Seeker (ARTS), an exploration engine for antibiotic cluster prioritization and novel drug target discovery, Nucleic Acids Research (2017).
2 Tackling Drug-Resistant Infections Globally: Final Report and Recommendations, The Review on Antimicrobial Resistance, May 2016.
3 Centers for Disease Control, 2013, https://www.cdc.gov/drugresistance/threat-report-2013/index.html