Warp Drive Bio is a leading company exploiting the molecules and mechanisms of nature to create transformative medicines. The company operates on the core principle that nature is the world's most powerful inventor of therapeutic agents, unconstrained by the mechanistic and synthetic limitations of traditional medicinal chemistry. Warp Drive Bio is deploying two proprietary platforms to discover and develop novel molecules addressing new pharmacologic mechanisms.
"We are reimagining the possible: drugging undruggable targets.”
Warp Drive Bio is developing a new drug modality, SMART™, based on a mechanism developed by nature. SMART™ enables small molecules to target human disease-causing proteins previously considered to be intractable to more traditional pharmaceutical modalities. It is estimated that >80% of human proteins cannot be targeted by conventional drug discovery approaches - small molecules and/or protein biologics - either because they are intracellular (inaccessible by biologics) or do not contain an involuted, hydrophobic binding site (required by small molecule drugs). SMART™ drugs overcome these limitations by functioning as an "intracellular biologic" therapeutic that can recognize and engage large undulating flat surfaces on intracellular targets.
SMART™ drugs are based on nature's chemistry and offer a solution to this vast set of biologically-validated, pharmaceutical opportunities. Briefly, they are able to penetrate cells where they bind to an intracellular receptor (the "presenter protein"). The resulting complex (SMART™ drug plus presenter) can then bind and modulate a specific intracellular target of interest. The surface properties of the SMART™ drug-presenter complex enable it to bind protein target surfaces through an interaction that recapitulates the mechanisms by which proteins naturally interact inside cells. SMART™ thus overcomes the limitations of small molecules to bind to such surfaces. SMART™ drugs combine the cell penetration properties of small molecules with the target-interaction mechanisms of protein biologics and can therefore access many of the >80% of human proteins that are not targeted by classical therapeutics.
Rapamycin is the natural prototypical SMART™ drug. It enters cells and forms a complex with FKBP, which can then bind a flat undruggable surface on mTOR with high affinity and selectivity. This leads to inhibition of mTOR activity.
Warp Drive Bio's SMART™ platform is inititally focused on two oncology targets in the MAPK signaling pathway: the undruggable RAS GTPase and the kinase ERK. There are many biological targets and/or mechanisms with strong validation that have been intractable by conventional drug discovery methods and are thus considered undruggable. These targets/mechanisms represent a set of therapeutic opportunities aimed at adressing unmet needs across diverse diseases, including oncology, inflammatory diseases and metabolic diseases.
"We are not afraid to take on tremendous challenges in order to develop transformative medicines."
-Dylan, Associate Director
Warp Drive Bio is deploying a battery of state-of-the-art, genome mining technologies to access powerful natural molecules that have been historically "hidden" within microbes (natural products). The history of natural product discovery has taught us that most natural products derived from microorganisms cannot be detected under normal laboratory conditions. Warp Drive Bio has assembled a vast genomic database of over 135,000 strains with the potential to encode more than four million biosynthetic gene clusters. To exploit this expansive genomic resource, Warp Drive Bio has developed a proprietary "genomic search engine" that enables hidden natural products to be revealed on the basis of their genomic signature. We then deploy our "genomes to molecules" synthetic biology platform to engineer and express novel natural products, so they can be isolated and tested for biological impact. Warp Drive Bio is thus accessing for the first time the complete natural product armamentarium for drug discovery.
The focus of Warp Drive Bio's genome mining efforts is to identify entirely novel chemical classes of antibiotics (what we define as 'neomorph antibiotics') replete with new mechanisms of action. The global challenge of drug-resistant infections continually supports the need for new antibacterial medicines* and Warp Drive Bio is significantly expanding the set of molecules from which those can be developed.
For more information on Warp Drive Bio's genome mining approach, see our SIMB 2015 talk entitled Rapid Engineering of Secondary Metabolite Gene Clusters in the Genomic Era and our SIMB 2016 talk entitled Surveying Thousands of Actinomycete Genomes for Novel Biosynthetic Clusters.
A major drawback to traditional natural product discovery is that only the most abundant compounds that are produced in the fermentation step are readily identified, whereas compounds that are conditionally expressed go undetected. Reliance on this traditional discovery methodology has, for example, yielded the rediscovery of known antibiotics many times, with much time and effort wasted on "dereplication" of known compounds.
Warp Drive Bio's strategy for natural product drug discovery circumvents the limitations of previous approaches. Microbial genome sequencing has revealed the enormous biosynthetic capacity of Actinomycetes, with about 90-95% of all biosynthetic pathways being "silent" or "cryptic" under standard laboratory fermentation conditions. Genomic search within known molecular classes and identification of entirely novel biosynthetic gene clusters is facilitated in bacteria because the genes that produce the natural product are clustered.
Warp Drive Bio's Genome Mining™ Platform is predicated on high resolution genomic sequencing and the subsequent analysis of entire bacterial genomes, which enables both isolation of complete biosynthetic gene clusters regardless of their size and sophisticated genomic search methods based on contextual information provided by the complete genome. Furthermore, the biosynthetic logic of the natural product can be deciphered from the sequence of the gene cluster, thus allowing a prediction of the structural novelty of the molecule encoded by the cluster. Warp Drive Bio has developed and validated proprietary state-of-the-art tools to rapidly identify and isolate the molecule from a novel biosynthetic gene cluster as a bioactive compound of interest, so that it can be advanced into biological assays and potential drug development.
Our ultimate vision for this program is that we will identify the complete natural product armamentarium of the Actinomycete family, thus creating a unique new set of pharmaceutical chemical diversity with broad application in the discovery of new human therapeutics.