Drug Discovery

D. E. Shaw Research conducts drug discovery programs both independently and in collaboration with other biopharmaceutical companies and research laboratories. All of our computational work is performed in‑house using a combination of our special‑purpose Anton supercomputers and high‑speed commodity hardware. We do not maintain in‑house “wet lab” facilities, but routinely design experiments for execution under our direction by various specialized contract research organizations (CROs).

Our drug discovery activities fall into three categories, each of which is enabled in part by the use of Anton‑based MD simulations, machine learning methods, and other advanced computational technologies:

  • Elucidating the molecular mechanisms of pathological biological processes
    • Identifying previously undiscovered biomolecular phenomena that may be relevant to the pathogenesis of potentially treatable human diseases
    • Determining how the binding of a given molecule at a given binding site modulates the function of a protein implicated in a given disease
    • Exploring at an atomic level of detail the effects of inherited or acquired mutations that are known to be associated with certain pathologies
  • Identifying new molecular strategies for pharmaceutical intervention
    • Discovering potentially druggable three‑dimensional protein configurations that have been inaccessible to experimental structure determination
    • Finding new, previously untargeted binding sites, including cryptic or ephemeral binding pockets and novel sites for allosteric modulation
    • Identifying ligand features that tend to stabilize or destabilize particular protein structures, or to promote or preclude particular interactions
  • Creating novel, precisely targeted, highly selective drugs
    • Using a combination of computational and experimental techniques to generate or screen small‑molecule compounds
    • Designing highly selective compounds that bind strongly to the target protein while avoiding toxicity‑inducing interactions with related proteins
    • Predicting and optimizing biopharmaceutical properties such as solubility and membrane permeability

Our research, technologies, and pharmaceutical expertise have each played an important role in bringing four drugs into clinical trials. We designed one of these drugs independently, and internally managed its early clinical development. The other three were discovered under a multi‑target collaboration and licensing agreement with Relay Therapeutics (NASDAQ: RLAY), a separate company of which D. E. Shaw Research was a co‑founder.

Our first independently developed drug, DES‑7114, is an orally administered medication that inhibits the ion channel protein Kv1.3 in a highly selective manner. This first‑in‑class therapeutic has demonstrated efficacy in preclinical models of several chronic inflammatory and autoimmune diseases, including ulcerative colitis, Crohn’s disease and atopic dermatitis, and successful Phase 1 clinical trials in healthy human volunteers were completed in early 2022. In May 2022, we entered into an exclusive global license agreement with Eli Lilly for further clinical development and commercialization of our program of Kv1.3‑targeted therapeutics, including DES‑7114.

The three drugs on which D. E. Shaw Research collaborated with Relay Therapeutics are all designed for the treatment of cancer, but each is aimed at a different cancer‑associated protein. RLY‑4008 targets the receptor tyrosine kinase FGFR2, which is frequently altered in certain malignancies; RLY‑2608 is designed to be the first allosteric, pan‑mutant (H1047X, E542X and E545X) and isoform‑selective PI3Kα inhibitor; and RLY‑1971 is designed to bind and stabilize the protein tyrosine phosphatase SHP2 in its inactive conformation. In December 2020, Relay entered into a worldwide license and collaboration agreement with Genentech for the development and commercialization of RLY‑1971. (To learn more about Relay, click here.)

D. E. Shaw Research welcomes the opportunity to collaborate with other pharmaceutical and biotech companies on the discovery and development of novel therapeutics.