Challenging Targets

Disease Areas c-Myc is a master regulator of cell growth and is aberrantly upregulated in over 70% of human cancers , including high-incidence malignancies like breast, colorectal, lung, and many others.

Challenges: Myc has long been deemed “undruggable” due to its lack of a stable binding pocket (it’s an intrinsically disordered protein) and its nuclear localization (making antibody therapies infeasible) . Unlike enzymes or receptors, Myc is a transcription factor that functions via protein–DNA and protein–protein interactions, giving macrocyclic natural products a few potential footholds to bind.

Disease Areas: β-Catenin is the key effector of Wnt signaling, a pathway abnormally activated in many cancers such as vast majority of colorectal cancers, liver cancers, some lung cancers, and fibrosis and regenerative disorders.

Challenges: β-Catenin has traditionally been considered “undruggable.” It is a multi-domain protein that mediates protein–protein interactions (e.g. with TCF/LEF transcription factors) rather than having an active site. Parts of the protein (such as its N-terminus) are flexible, and the crystal structure of some regions is lacking, complicating structure-based design. Overall, β-catenin presents a “featureless” surface with no obvious small-molecule pockets . Past efforts to inhibit β-catenin’s nuclear activity or destabilize it have struggled with specificity and potency.

Disease Areas: p53 is a tumor-suppressor protein mutated in over 50% of all tumors making it arguably the most frequently altered driver of cancer. Loss of p53 function allows cancer cells to evade apoptosis and accumulate DNA damage. A therapy that restores or mimics p53 function could therefore have broad application across many cancer types such as lung, colorectal, breast. Additionally, modulating p53 pathways has implications in degenerative diseases and aging.

Challenges: p53’s “undruggable” reputation comes from multiple factors. p53 is a DNA-binding protein with numerous mutants with distinct structural defects that make it difficult to target. While the core DNA-binding domain of p53 has a known structure, many mutants destabilize this domain, and p53 also has disordered regions. Designing a drug to refold or reactivate mutant p53 is exceptionally challenging.

Disease Areas: RAS proteins (KRAS, NRAS, HRAS) are among the most commonly mutated oncogenes, with RAS mutations present in ~30% of all human cancers. KRAS in particular is a driver in major cancers: ~90% of pancreatic adenocarcinomas, ~30–40% of colorectal cancers, and ~20–30% of lung adenocarcinomas harbor RAS mutations.

Challenges: RAS was long the poster child of “undruggable” proteins. The KRAS protein is a small GTPase with a mostly smooth, globular structure – often likened to a “featureless tennis ball” – lacking the deep pockets where a drug might bind. Moreover, RAS binds its natural ligands (GTP/GDP) with picomolar affinity, outcompeting most small molecules . The challenge was especially acute because RAS’s surface is needed for binding essential regulators (GEFs, GAPs) and effectors; disrupting those interactions without a clear pocket was extremely difficult.

Disease Areas & Market Opportunity: STAT3 is a transcription factor that mediates signaling for a broad range of cytokines and growth factors (like IL-6) in both cancer and inflammation. It is persistently activated in most human cancers – promoting tumor cell proliferation, survival, angiogenesis, and immune evasion. STAT3 is also implicated in autoimmune and inflammatory diseases (due to its role in regulating T cells, macrophages, fibrotic processes, etc.). Thus, a STAT3 inhibitor could have dual markets: oncology (solid tumors, lymphomas) as well as immune-mediated conditions (rheumatoid arthritis, psoriasis, fibrosis) . Each of these areas represents a large and growing market, and a drug addressing STAT3-driven pathways could become a platform therapy across multiple indications.

Challenges: Like other transcription factors, STAT3 has been considered “undruggable” for years. It does contain a known SH2 domain (which it uses to dimerize upon activation), but efforts to block this domain with small molecules faced issues of potency and selectivity. One challenge is that STAT3’s structure is highly homologous to other STAT family members, so finding molecules that specifically hit STAT3 without off-target effects on STAT1/STAT5 is difficult . Additionally, early STAT3 inhibitor chemotypes had poor cell permeability or caused toxicity, reflecting how tricky this target has been. The result is that despite clear biological importance, no STAT3 inhibitor has yet reached approval.

Disease Areas & Market Opportunity: Tau is a microtubule-associated protein that aggregates abnormally in Alzheimer’s disease (AD) and related tauopathies such as frontotemporal dementia and progressive supranuclear palsy. In AD, tau pathology correlates with neurodegeneration and cognitive decline, and tracking tau burden is increasingly used as a clinical biomarker. Therapeutically, targeting tau could complement or offer alternatives to amyloid-based strategies.

Challenges: Tau is intrinsically disordered and lacks a stable 3D structure, which complicates structure-based drug design. It aggregates into intracellular beta-sheet-rich filaments and adopts multiple conformations, making it hard to define a consistent binding pocket. Tau's normal role in microtubule stabilization adds another layer of complexity. Most small-molecule tau aggregation inhibitors and kinase inhibitors aimed at reducing tau phosphorylation have failed in clinical trials. Additionally, tau is localized intracellularly, limiting the utility of biologics, though some antibodies are being explored to target extracellular tau species.