Developing small molecule drugs against "undruggable" protein targets

Cancer remains a major global health challenge and is the second leading cause of death in the United States, with projections suggesting it may soon surpass heart disease. Globally, over 52,900 people are diagnosed with cancer every day, and more than 27,000 succumb to it. By 2040, the world is expected to witness 28 million new cancer cases and 16.2 million deaths annually.

In response, scientists, clinicians, and pharmaceutical industries have mounted a comprehensive campaign to develop better cancer treatments. The global market for anti-tumor drugs is projected to grow at an annual rate of nearly 5%, increasing from $94 billion in 2022 to $126 billion by 2029. A recent review highlighted several key trends in cancer drug development, emphasizing new therapeutic strategies:

• Specialization of Tumor Drugs: New drugs target specific cancer mechanisms such as angiogenesis inhibition, tumor metabolism, and immune system modulation, moving beyond the broad, often toxic effects of traditional chemotherapy, which broadly inhibit cell replication and proliferation.
• Shift from Small Molecules to Large Molecules: While small molecules remain vital, there is a growing use of larger molecules like peptides, antibody drugs, and cell therapies, which allow for more precise treatment.
• Focus on Immune Activation (immunotherapy): Many new treatments are designed to harness and activate the patient’s immune system, as seen with antibody-drug conjugates, CAR-T, and anti-PD-1 therapies.
• Combination Therapies: Increasingly, treatment protocols combine multiple strategies, integrating immunotherapy, targeted therapy, and traditional chemotherapy for more effective outcomes.
• Diverse Treatment Approaches: The development pipeline now includes therapies targeting previously "undruggable" proteins, as well as peptide drugs, monoclonal antibodies, cell and gene therapies, cancer vaccines, and oncolytic viruses.

While much attention has shifted to large macromolecule drugs, significant progress is still being made in the small molecule drug arena. Small molecules have distinct advantages: they are generally easier and less costly to synthesize, can be administered orally, and most importantly, due to their small size, they can penetrate cell membranes—something that large molecules like antibodies cannot achieve as easily.

One of the most groundbreaking advancements has been the ability to target and inhibit proteins that were previously considered "undruggable" by small molecules. These proteins, involved in critical cancer pathways, were difficult to target for several reasons:

• Lack of Suitable Binding Pockets: Many undruggable proteins lack well-defined pockets where small molecules can bind to effectively inhibit function.
• Protein-Protein Interactions (PPIs): Many cancer-driving proteins are involved in large, flat, and dynamic protein-protein interfaces, which are difficult for small molecules to target.
• Dynamic and Flexible Structures: Some proteins have flexible structures, making it challenging to design drugs that can consistently bind and alter their function.

Despite these challenges, innovative drug design strategies have begun to address previously untreatable targets, unlocking new avenues for cancer therapy. For example, the KRAS protein, a key player in cancer, was historically considered undruggable. However, breakthroughs led to the development of KRASG12C (a particular oncogenic KRAS mutant) inhibitors, such as sotorasib and adagrasib, which have shown promise in treating non-small cell lung cancer, as well as other cancers. Some of these new strategies include the following:

• Covalent Modulation: This approach involves designing drugs that form irreversible covalent bonds with their target proteins, stabilizing drug-protein interactions (Figure 1). Covalent inhibitors like AMG 510 (sotorasib) have successfully targeted KRAS mutations, marking a milestone for treating previously untreatable cancer drivers.
• Allosteric Inhibition: Rather than directly targeting active sites, allosteric inhibitors bind to alternative sites on proteins, inducing conformational changes that inhibit protein function. Drugs such as asciminib (used for chronic myeloid leukemia) and cobimetinib (used for melanoma) exemplify this strategy.
• PROTACs (Proteolysis-targeting chimeras): PROTACs represent a novel approach by linking target proteins to E3 ubiquitin ligases, which mark the proteins for degradation. Early-stage trials for PROTACs, such as ARV-110 and ARV-471, have shown potential in targeting tumor-specific proteins, although challenges with size and permeability remain.
• Molecular Glue Degraders (MGDs): MGDs also promote the degradation of cancer-driving proteins but do so by facilitating interactions between the target protein and E3 ligases. Several MGDs are currently undergoing clinical trials for solid tumors and lymphomas, offering another promising avenue for treating difficult cancers.

PROTACs and MGDs are related in that they both promote degradation of the target by facilitating interaction with an enzyme that helps to degrade proteins (E3 ligase), but they differ in how they achieve this objective. PROTACs use a bifunctional molecule with a linker, whereas MGDs promote a direct, glue-like interaction between the target and the ligase. Because of their bifunctional nature, PROTACs tend to be larger than MGDs, and easier to design.

Despite these innovations, obstacles remain. Drug resistance, particularly in targeted therapies like those for EGFR, continues to be a significant challenge, requiring new treatment strategies; "undruggable" proteins like more typical druggable protein targets can acquire mutations so that the small molecule can no longer bind. Additionally, the design of small molecule inhibitors for proteins within homologous families remains complex due to their structural similarities. Ensuring that these inhibitors are both effective and safe, while minimizing side effects, will be critical to the success of future cancer therapies.

In summary, small molecule drugs are playing a critical role in advancing cancer treatment by targeting previously unreachable proteins, offering hope for more effective and personalized cancer care. 

Figure 1. An "undruggable" protein may possess a shallow active site so that a small molecule has difficulty interacting with the protein in a stable fashion. A covalent inhibitor can form a covalent bond between the small molecule inhibitor and the protein target resulting in stable inhibition (Wikipedia).