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Undruggable or Just Undrugged? Exploring Alternative Targets

The world of drug discovery continues to evolve with changes in the availability of analytical tools and reagents and new strategies leveraged to pursue molecular targets previously considered to be undruggable. This is especially true in oncology where there are large numbers of challenging molecular targets identified but not yet exploited for pharmacological intervention.

So says SLAS2017 Session Chair John S. Lazo, Ph.D., professor at the University of Virginia School of Medicine and director of the Fiske Drug Discovery Laboratory, who is helping to debunk the concept that certain molecular targets are undruggable. He prefers to consider these targets undrugged and with this reclassification, hopes to shift scientific perspective and to stimulate even more thoughtful consideration and exploration of alternative strategies.

With more than 20 years invested in the fields of pharmacology and drug discovery, Lazo says, “My philosophy about academic research is that we should be doing things that industry and biotech aren’t doing. The high-risk, challenging molecular targets that sometimes are called undruggable are exactly the areas where we like to play.” His group works primarily in the oncology sector and is currently focused on protein tyrosine phosphatases – one of the prototypical classes of undrugged targets in cancer biology.  

But What Does Undruggable Really Mean?

As scientists in the field of drug discovery know, druggable targets for pharmaceutical intervention have often been proteins with an enzymatically active site to which a small molecule could bind. Binding would block activation, alter biologic activity and modulate a disease state. Targets falling outside this narrow description have often been considered undruggable. Lazo says, “it is unbelievable how easily the soil gets salted in this field” and notes in a recent publication that “the suitability of a particular molecular target for drugging has been heavily influenced by existing precedence.”

He says the concept of druggability, however, is evolving. While still associated with some degree of controversy, a number of research groups are expanding their thoughts about what is druggable as they explore targets for which there has not yet been a successful therapeutic developed.

Large numbers of potential drug targets for cancer have been discovered but the vast majority do not fit the conventional “lock and key” model. These targets have been considered inaccessible to manipulation and therefore undruggable. These targets often function through protein-protein interactions, adaptor proteins, transcription factors and non-protein targets. Lazo notes, “In the area of cancer, we have a very high fraction of drugs in clinical trails going after some pretty challenging targets.”

Current Examples of Undrugged Cancer Targets

Lazo’s recently published paper “Drugging Undruggable Molecular Cancer Targets” discusses these ideas and highlights examples of three general classes of molecular targets for which progress towards druggability is being made. The three classes of target compounds discussed are phosphatases, transcription factors and RAS.


Protein phosphatases counterbalance the enzymatic activity of protein kinases and both play a central role in cancer cell survival and response to drug treatment. There are approximately five times more kinases than phosphatases. The FDA has approved numerous kinase inhibitors as cancer therapeutics and more are in clinical trials. In contrast, there are no FDA-approved drugs that regulate protein phosphatases and only one compound is currently in an early phase trial.

The phosphatase LB100, a PP2A inhibitor is in Phase I trial as an indication against solid tumors. A recent review article summarizes pre-clinical studies that demonstrate anti-cancer activity against glioblastoma, sarcoma, pheochromocytoma, breast cancer, nasopharyngeal carcinoma, hepatocellular carcinoma, pancreatic cancer and ovarian cancer. The compound enhances the effects of chemo- and radiotherapies with end consequences of enhanced tumor permeability to drug exposure, induction of cell differentiation and tumor cell death resulting from apoptosis. Lazo notes in his paper that LB100 is “one of the only phosphatase inhibitors currently in clinical trials for cancer.”

In the same paper, Lazo explains that there are several factors contributing to the dearth of protein phosphatases in the drug development pipeline. “It was once thought that phosphatases were only constitutively expressed enzymes with little regulatory role in homeostasis or disease-a notion that has largely been debunked.” Also, individual phosphatases were thought to act only as tumor suppressors and unable to contribute to cancer development. As is often the case in biological systems, the roles of these compounds in this complex homeostatic system are more dynamic than was initially understood. Both of these ideas have proven to be untrue, thus clearing the way to investigate phosphatases as therapeutic targets in oncology.

Lazo’s group is working with phosphatases and he pointed out the recently published success of a group at the Novartis Institute for Bio-Medical Research that identified a novel approach to blocking activation of the phosphatase, SHP2. SHP2 helps promote tumor growth when it adopts an open conformation. The Novartis group identified a compound that binds to the outside of the molecule in its closed (inactive) conformation and prevents the protein from opening to reveal the active site. This is an example of noncompetitive of allosteric inhibition. If the compound cannot adopt the open conformation, it cannot be activated and is unable to promote cancer growth. Lazo says “These new allosteric inhibitors really represent the second or third generation of inhibitors that may actually be useful.”

Transcription Factors

Transcription factors (TF) are integral to intracellular signaling processes leading to gene expression and may be directly or indirectly involved in cancer-associated alterations. TFs form protein complexes that interact with specific DNA sites. Lazo explains in his paper “the sites on TFs involved in these interactions are generally large, flat surface areas, in contrast to the deep, druggable binding pockets found on most enzymes or receptors.” Current strategies aim to prevent interactions between proteins and therefore disrupt the TF-DNA binding. Within this class, two of the big players are c-MYC and p53.

As a regulator gene, c-MYC codes for a TF involved in cell cycle progression, apoptosis and cellular transformation. MYCs activity is regulated through formation of MYC:MAX heterodimers that play an important role in a wide range of normal cell functions. This raises concerns about the possibility of inhibiting functions too broadly and causing unacceptable toxicities. Approaches to disrupt or stabilize the dimers in this system as well as inhibition of c-MYC are being explored. A lipid nanoparticle formulation of c-MYC siRNA (DCR-MYC) that inhibits c-MYC translation is currently in Phase I clinical trials for hepatocellular carcinoma.

The tumor suppressor TF, p53, is the most frequently mutated gene in human cancers and is therefore a highly valued target for cancer therapy. p53 regulates processes such as DNA repair, metabolism, cell cycle arrest, apoptosis and senescence. When these functions are lost, cells become dysregulated and malignancies develop. Several approaches are being investigated that include restoring the active conformation of mutant p53 leading to apoptosis of the cancer cells and blocking binding of the regulating molecules that promote p53 degradation. There are a number of small molecules that inhibit p53-protein interactions progressing in pre-clinical trials.


Another significant target in cancer biology is RAS, which has proven doggedly resistant to drugging for several decades. Mutated in three of four of the most lethal human malignancies (colon, lung and pancreatic cancer), Lazo spotlights  RAS as a “highly prized cancer drug target” but it has been very challenging because of its interaction in the plasma membrane, lipid post-translational modifications and involvement in complex signaling pathways.

Protein-Protein Interactions

A commonality among some of the undrugged molecular targets is that their functionality is derived from interacting with other proteins or large molecules (like DNA). These interactions have been challenging to address but are an important target for developing anticancer strategies. Haian Fu, Ph.D., professor at Emory University and member of the Emory Chemical Biology Discovery Center, says “proteins network just like human beings” when discussing anticancer strategies. Cellular signaling pathways and networks rely on protein-protein interactions to carry out their functions. In his work to discover novel cancer related protein-protein interactions, he uses high-throughput screening systems to interrogate large numbers of compounds. High-throughput systems enable researches to leverage the advances in genomics and accelerate the process of therapeutic discovery. The figure below (from an interview with NCIs Office of Cancer Genomics) summarizes the overall process.









Credit: Haian Fu, Emory University and previously published in National Cancer Institute Office of Cancer Genomics e-newsletter, Issue 10, October 2013.

Scientific Advances Supporting Contemporary Discoveries

From Lazo’s paper on drugging the undruggable:


The explosion of molecular oncology targets, from oncogenes and tumor suppressors to regulators of metastasis and immunological responses, has transformed cancer pharmacology. There continues to be an intense effort to identify new validated therapeutic targets. Large groups of candidate drug targets have been ignored, however, because they are perceived as inaccessible to pharmacological manipulation. Listed below are some of the advances that have countered this perception.

Although issues remain with approaching some molecular oncology targets, there are encouraging signs that the landscape is changing.

Analytical and computational power has become more accessible to researchers. The increased availability of protein NMR and crystallography have given scientists vast amounts of new data about protein structures and improved computational power has aided visualization of dynamic aspects of molecular targets.  

The development of libraries of millions of compounds of highly diverse compounds (from peptides to small molecules) has evolved to incorporate three-dimensional properties to simulate binding sites on protein targets. Coupling these reagents with high-throughput screening systems with enhanced physiological relevance makes for a powerful combination. These have, in part, helped to elucidate more detailed information about cell signaling pathways, revealing additional complexity along the way.

Additionally, there is a trend in drug discovery to create more physiologically relevant assay systems to evaluate compounds of interest earlier in the discovery process. Cell-based assays are commercially available and more sophisticated systems are in development.

Ongoing Challenges

Even as technology and scientific understanding progress, there remain many challenges for the community involved in drug discovery whether in the private or public sector. Lazo notes, “there is no unifying organization for undruggable targets” so researchers may feel like a “solo practitioner out there saying, ‘trust me this is going to work.’” To that end, SLAS is making strides in bringing people together to exchange information and advance scientific research. Both private and public research centers are banding together to share resources and knowledge. Michelle Arkin, Ph.D., professor at the University of California, San Francisco, is one of many SLAS members who thrive on finding the common thread between apparently disparate ideas and bringing people together to solve problems.

Lazo also talks about a cultural challenge. He feels “we do not [always] recognize the significance of some of the scientific observations that are really impressive and that we need to encourage the risk-takers who are going after the brand new targets that are really challenging.” He would like to see a drug discovery culture “that celebrates these major advances when they come along, without too much hype, but to truly recognize how important they are to the culture of drug discovery.” He considers the breakthrough of the Novartis group with SHP2 mentioned above under Phosphatases as an example of something important.

There is a move toward more phenotypic screening that presents an opportunity for growth as investigators probe the complex signaling networks within cancer cells. Lazo is “intriqued with the availability and content of single cell methods that are available to do phenotypic screens” and thinks we need to better understand what sorts of animal models are most clinically relevant.

And funding. Lazo talked about the challenges in getting funds for research. Whether seeking public grants or corporate allocations, he feels there is stiff competition for funds in all arenas. He notes, there is reluctance to fund things that haven’t been proven, creating a Catch-22 scenario. Despite some exceptions, funding for unproven approaches in both the private and public sector remains a barrier to exploration of a greater range of targets.

Historically, “we put a very high premium . . . on highly selective drugs” says Lazo. But we know from the COX-2 failure that highly selective drugs are not always better than less selective, “dirty” drugs. “The challenge is that we are not going to be just drugging one target,” he says. “We are probably trying to drug a couple of targets at a time and how do you efficiently embed that process as you go forward? What is the right constellation of targets? Being able to understand what your compound really does, off target and on target and how important that ‘off target’ effect is, is going to be a challenge.”

Despite the challenges, Lazo speaks enthusiastically about the people doing excellent, groundbreaking work and he feels these are exciting times in research and drug discovery.

Learn More

Lazo is chairing a session in the SLAS2017 Assay Development and Screening Track to highlight screening approaches and tools that enable development of “undrugged” molecules.

“The concept of druggability is a controversial one. Whilst the majority of marketed drugs come from a few target classes, novel therapeutics are being progressed that act on protein-protein interactions, adaptor proteins, transcription factors as well as non-protein targets. We will discuss this in the context of screening approaches and tools that enable the identification and development of molecules acting via mechanisms previously thought to be undruggable.”


John Lazo photo credit in article banner: Amy Jackson.

October 17, 2016