On June 1, 2011, Cambridge Healthtech Institute’s (CHI’s) Insight Pharma Reports announced the publication of our new book-length report, Multitargeted Therapies: Promiscuous Drugs and Combination Therapies.

In the past 20 years or so, pharmaceutical and biotechnology industry R&D has been increasingly aimed at developing drugs to treat complex diseases such as cancer, cardiovascular disease, type 2 diabetes, and Alzheimer’s disease. However, the one drug-one target-one disease paradigm that has become dominant in the post-genomic era has proven to be inadequate to address complex diseases, which have multiple “causes”, and each of which may be more than one disease. This has been a major cause of clinical failure and the low productivity of the pharmaceutical industry.

Moreover, researchers have found that most of the successful, FDA-approved small-molecule drugs that were developed prior to the year 2000 are promiscuous, i.e., they are single drugs that address multiple targets. In addition, the great majority of kinase inhibitors, one of the most successful drug classes of the early 21st century, are also promiscuous.

The study of small-molecule drug promiscuity has spawned the emerging field of network pharmacology, which can be applied both to study drug promiscuity and to rationally design small-molecule multitargeted drugs. (Researchers can discover or design multitargeted kinase inhibitors without the use of network pharmacology, however.)

Meanwhile, the development of targeted drugs such as kinase inhibitors and monoclonal antibodies has resulted in the need to develop multitargeted combination therapies. This has been especially true in cancer, where disease causation may involve multiple signaling pathways. In particular, the development of resistance to targeted antitumor drugs has spawned the need to develop second-generation treatments, many of which are multitargeted combination therapies.

Our report covers both discovery and design of small-molecule promiscuous/multitargeted drugs, and of multitargeted combination therapies.

The design of multitargeted combination therapies is one of the hottest areas of cancer R&D today, especially with respect to developing means to overcome resistance to targeted therapies. This area was the focus of many key presentations at the 2011 American Society of Clinical Oncology (ASCO) Annual Meeting, which was held in Chicago on June 3-7. For example, treatment with vemurafenib (PLX4032) of metastatic melanoma patients whose tumors carry the B-Raf(V600E) mutation has produced spectacular overall response rates and increased survival. However, in nearly all cases, the tumors relapse. The latest results with vemurafenib were discussed at ASCO 2011, as well as strategies to overcome resistance to therapy. Our new report also discusses strategies for overcoming vemurafenib resistance, all of which involve design of multitargeted combination therapies.

Another topic discussed at ASCO 2011 was antitumor strategies based on synthetic lethality. We discussed this strategy in an earlier article on this blog, especially with respect to poly(ADP) ribose polymerase (PARP) inhibitors such as KuDOS/AstraZenaca’s olaparib. At a session at the ASCO meeting entitled “PARP Inhibitors, DNA Repair, and Beyond: Theory Meets Reality in the Clinic”, speakers reviewed current progress in developing PARP inhibitors, of which six are now in clinical development.

This session also included a presentation by Michael B. Kastan, MD, PhD (St. Jude Children’s Research Hospital, Memphis TN) on other ways of using the synthetic lethally strategy, for example by targeting kinases involved in DNA repair pathways such as ATM (Ataxia-Telangiectasia Mutated) or Chk1 checkpoint kinase, or even utilizing features of the tumor microenviroment such as hypoxia. Such strategies might be used to design multitargeted combination therapies that specifically target cancer cells with defects in DNA repair and/or in hypoxic solid tumors, and/or to sensitize cancer cells to radiation.

Our new report includes a chapter on using the synthetic lethality strategy to design combination therapies of a cytotoxic drug with a chemosensitizing agent, and to develop therapies for p53-negative cancers. (The key tumor suppressor p53 is deleted, mutated, or inactivated in the majority of human cancers).

Although design of multitargeted combination therapies, as well as discovery and design of kinase inhibitors, are of key importance for current oncology R&D and are also being applied to other diseases, design of single small-molecule multitargeted drugs via network pharmacology is an early-stage, and perhaps a premature, technology. Nevertheless, given the current pharmaceutical company R&D business model that emphasizes outsourcing early-stage R&D, academic research groups and biotechnology companies that are active in this area may be able to forge partnerships with pharmaceutical companies.

For more information on Multitargeted Therapies: Promiscuous Drugs and Combination Therapies, or to order it, see the Insight Pharma Reports website.


On November 27, 2009, we posted an article on this blog about the use of stapled peptides in targeting intracellular pathways. This technology was originally developed by Dr. Gregory Verdine (Department of Chemical Biology, Harvard University, Cambridge MA, and the Dana-Farber Cancer Institute, Boston MA) and his colleagues. A biotechnology company, Aileron Therapeutics (Cambridge, MA) was founded (with Dr. Verdine among its founders) in 2005 to develop and commercialize stapled peptide drugs. Aileron’s most advanced compounds, which are being developed for the treatment of solid and hematological tumors, are only in the preclinical stage.

On August 24, 2010, Aileron and Roche announced that they had entered into a collaboration to discover, develop, and commercialize stapled peptide drugs designed to address up to five undisclosed targets. These targets are selected from Roche’s key therapeutic areas of interest–oncology, viral diseases, inflammation, metabolic diseases, and central nervous system diseases.

Under the agreement, Roche will provide Aileron guaranteed funding of at least $25 million in R&D support and technology access fees. Aileron will also be eligible to receive up to $1.1 billion in discovery, development, regulatory, and commercialization milestone payments, if drug candidates are developed against all five targets. Aileron will also receive royalties on any future sales of marketed products that result from the collaboration.

In our November 2009 article, we discussed the design of stapled peptides, in which hydrocarbon moieties are used to constrain, or “staple” peptide sequences into an α-helical conformation. These sequences are designed to mimic key binding domains of proteins that are involved in intracellular signaling pathways. We gave two examples of pathways that were addressed by specific stapled peptides: the Notch pathway and a Bcl-2-related apoptotic pathway. In both cases, the stapled peptides modulated protein-protein interactions that are considered “undruggable” by conventional small-molecule drugs.

According to Roche, It is “as yet intractable” intracellular protein-protein interactions that are of special interest to the company in collaborating with Aileron.

According to Aileron, the new alliance with Roche validates the broad potential of their stapled peptide technology platform across multiple therapeutic areas and classes of targets. The alliance also provides Aileron with capital to advance its internal R&D.

The Roche agreement represents Aileron’s first Big Pharma strategic alliance. However, a venture capital consortium that included GlaxoSmithKline, Novartis, Roche, and Lilly invested $40 million in Aileron in June 2009.

As we said in our November 2009 article, stapled peptides represent an exciting and innovative technology with the potential to address “undruggable” protein-protein interactions, even though the therapeutic value of stapled peptides has not yet been confirmed in the clinic. (We have discussed several other means of addressing protein-protein interactions in various articles in this blog–these targets represent an area of opportunity for companies that are innovative enough to pursue it.) And as we discussed in a more recent article, Roche is one of the Big Pharma companies that continues to be focused on innovative drug discovery and development, in an era of Big Pharma R&D retrenchment. The Aileron-Roche partnership therefore appears to be an ideal match.

In our March 2, 2010 blog post, we focused on a Phase I clinical trial of Plexxikon/Roche’s PLX4032, in which clinical researchers led by Keith T. Flaherty achieved a dramatic breakthrough in treatment of metastatic melanoma. Now we shall discuss the discovery of the drug itself, PLX4032.

In 2002, a research consortium based at the Wellcome Trust Sanger Institute in the U.K. found B-Raf somatic missense mutations in 66% of malignant melanomas (as well as in a subset of other cancers). V600E (valine substituted by glutamic acid at position 600) accounted for 80% of these mutant forms of B-Raf. The V600E mutation causes destabilization of the inactive conformation of B-Raf kinase, shifting the equilibrium toward the catalytically active conformation.

B-Raf is a serine/threonine protein kinase that is a component of an intracellular pathway that mediates signals from growth factors. B-Raf is regulated by binding to Ras. In turn, B-Raf activates MEK (mitogen-activated protein kinase kinase), which activates ERK (extracellular signal-regulated kinase). Activated ERK goes on to upregulate transcriptional pathways that promote cellular proliferation and survival.

Growth factors → →Ras→ B-Raf→ MEK→ ERK→ →upregulation of cell proliferation and survival

Growth factor signaling via Ras also controls other signaling pathways that upregulate cell proliferation, notably the PI3K-Akt (phosphatidylinositol-3-OH kinase-Akt) pathway.

The Sanger researchers found evidence that cells carrying B-Raf(V600E) no longer require Ras function for proliferation. This would mean that melanoma cells carrying this mutation could proliferate independently of growth factor signaling, resulting in the runaway proliferation characteristic of the malignant phenotype.

These results suggested that B-Raf(V600E) would be a good target for novel kinase inhibitors to treat malignant melanoma. The first such kinase inhibitors to be developed, although they had inhibitory activities at low nanomolar concentrations against B-Raf (both wild-type and mutant), were not successful in the clinic, due to their inhibition of multiple nonspecific targets and/or their poor bioavailability. Plexxikon researchers therefore set out to discover inhibitors that are highly selective for B-Raf(V600E). The result was the discovery of PLX4032.

The discovery of PLX4720 (a tool compound or chemical probe related to PLX4032) by Plexxikon researchers and their academic colleagues, and its preclinical validation, is described in a 2008 publication, Tsai et al. Plexxikon used its proprietary “scaffold-based drug design” technology platform to discover PLX4720. Scaffold-based drug design involves synthesizing sets of low-molecular weight “scaffold-like’” compounds. These compounds interact (typically at low affinity) with many members of a protein family by targeting their conserved regions.

In the B-Raf study, the researchers identified protein kinase scaffolds by screening a select library of 20,000 150-350-dalton compounds for inhibition of a set of three structurally characterized protein kinases at a concentration of 200 micromolar (μM). Of this library, 238 compounds were selected on the basis of their inhibition of the kinases by at least 30% at the 200 μM concentration. Each of the compounds was cocrystallized with one if the three kinases, Pim-1. Using this method, the researchers found that 7-azaindole bound to the ATP-binding site of Pim-1 kinase. They further modified this compound by adding side chains on the 3 position of 7-azaindole, resulting in a “scaffold candidate” with increased affinity for the ATP binding site of PIm-1 and other kinases. The researchers further modified this scaffold, based on structural data from other kinases. Ultimately, they cocrystallized their modified compounds with wild-type B-Raf and B-Raf(V600E), and optimized the structure of their compounds to give a compound, PLX4720, with selectivity for B-Raf(V600E) and against wild-type B-Raf and other kinases. This process (including the relevant chemical and protein structures) is illustrated in Figure 1 of Tsai et al.

In biochemical assays, the researchers found that PLX4720 inhibited B-Raf(V600E) at low nanomolar concentrations, and was 10-fold more selective for B-Raf(V600E) than for wild-type B-Raf, and was even more selective for B-Raf(V600E) than for other kinases.

Surprisingly, in cellular assays, PLX4720 is over 100-fold (not 10-fold) more selective in inhibiting proliferation of tumor cell lines that bear B-Raf(V600E) as compared to those that bear wild-type B-Raf. Moreover, as first found by researchers at Pfizer and their academic collaborators, a specific inhibitor of MEK (Pfizer’s CI-1040) is also similarly selective for tumor cell lines bearing B-Raf(V600E). This suggests that the B-Raf-MEK-ERK pathway is critical for the proliferation of B-Raf(V600E) cells, but not for cells bearing wild-type B-Raf. [For example, tumor cells that bear wild-type B-Raf might use the PI3K-Akt pathway to upregulate pathways that control cell proliferation independent of ERK signaling, while tumor cells that bear B-Raf(V600E) cannot.]

The B-Raf-MEK-ERK pathway dependence of B-Raf(V600E) cells may in part be related to feedback inhibition of B-Raf (and other isoforms of Raf). Activated ERK can phosporylate wild-type Raf isoforms at specific inhibitory sites. This results in downregulation of signaling via the Raf-MEK-ERK pathway. However, in cells bearing B-Raf(V600E), this feedback inhibition is disabled, resulting in uncontrolled signaling.

The Plexxikon researchers (Tsai et al.) tested PLX4720 against tumor xenograft models. Oral administration of PLX4720 blocked tumor growth, and in 4 out of 9 cases caused tumor regressions, in mice with tumor xenografts bearing B-Raf(V600E). Treatment with PLX4720 was well tolerated, and showed no adverse effects. Growth of tumor xenografts bearing wild-type B-Raf was not affected by PLX4720. In mice with tumors bearing B-Raf(V600E), PLX4720 blocked B-Raf-MEK-ERK pathway signaling, as demonstrated by immunohistochemical assays.

The exquisite specificity of PLX4720/PLX4032 for B-Raf(V600E) as compared to wild-type B-Raf was made possible by Plexxikon’s structure-guided “scaffold-based drug design” technology. Other structure-guided drug design technologies, such as fragment-based lead design, as is carried out in several companies, might be used to design comparably specific drugs.

The discovery of PLX4720/PLX4032 is an example of the use of new-generation chemistry technologies (or the revival of the old, and now disused natural products chemistry approach), coupled with biology-driven drug discovery strategies, to discover promising new drugs. We have discussed this strategy in several articles on this blog. (For example, see here and here).

Despite the promising results seen in Phase I clinical trials of PLX4032, it must be emphasized that the establishment of the efficacy and safety of this compound awaits the completion of the ongoing Phase III trials. Moreover, despite the dramatic regressions and increased survival seen in the Phase I trials, all the patients apparently eventually suffered relapses. Dr. Flaherty, as discussed in our earlier blog post, sees the need for combination therapies to effectively combat metastatic melanoma. In early 2009, Dr. Flaherty and his colleague Keiran S Smalley published a mini-review on potential strategies for developing such combination therapies.

In our November 27th blog post, we discussed an innovative new technology, stapled peptides, for use in targeting intracellular protein-protein interactions. In the example we gave, the target was a transcription factor complex in the Notch pathway. As we stated, protein-protein interactions are deemed to be “undruggable”, since they cannot be readily addressed with small molecule drugs.

Nevertheless, in some cases, small molecules have been discovered that do address key protein-protein interactions, and which may become clinical candidates.

Back in February 2006, Decision Resources published our report, “Protein-Protein Interactions: Are They Now Druggable Targets?” Among the case studies we discussed in that report was one in which researchers were attempting to discover small-molecule agents that targeted the Wnt pathway. The researchers discovered small-molecule agents that, as with the stapled-peptide example we discussed in our previous blog post, targeted a transcription factor complex. As of late 2009, two of these compounds are in preclinical development for treatment of various cancers.

Mutations that mediate deregulation of the Wnt pathway are causative factors in several types of cancer, most notably colorectal cancer, as well as multiple myeloma (MM), hepatocellular carcinoma (HCC), and B-cell chronic lymphocytic leukemia B-CLL). In the canonical Wnt pathway, soluble extracellular factors that are members of the Wnt family activate the pathway. A complex that includes the protein adenomatous polyplosis coli (APC) is central to the Wnt pathway. When Wnt receptors are not engaged by their ligands, kinases in the APC complex phosphorylate β-catenin, a multifunctional protein that is involved both in signal transduction and in adhesion between cells. Phosphorylation targets β-catenin for degradation.

When Wnt proteins bind to their receptors, the kinase activity of the APC complex is inactivated. This results in the accumulation of β-catenin, which moves into the nucleus. There it binds to proteins of the T cell factor (Tcf) family. β-catenin binding changes Tcf from a transcriptional repressor into a transcriptional activator. Downstream genes controlled by the β-catenin/Tcf complex include the oncogene Myc and other genes that mediate cell proliferation.

In precancerous colonic adenomas or the colorectal cancers that they may evolve into, APC is usually mutated. This results in constitutive stabilization of β-catenin and constitutive activation of Tcf and its downstream genes. In other types of cancer that involve constitutive Wnt pathway activation, β-catenin also becomes stabilized, via other means. This makes the Tcf/β-catenin a tempting target for drug discovery. However, it is a protein-protein interaction, and is thus deemed “undruggable”.

In 2004, A group led by Ramesh Shivdasani (Harvard Medical School, Dana-Farber Cancer Institute, and Brigham and Women’s Hospital, Boston MA), including researchers from the Novartis Institutes for BioMedical Research (Cambridge, MA), discovered several small-molecule inhibitors of the interaction between human Tcf4 and human β-catenin.

Dr. Shivdasani’s group, among others, had previously determined crystal structures of Tcf-β-catenin complexes. The interaction between the two proteins occurs over a large surface area. It is the large, and usually hydrophobic, interface between proteins in protein-protein interactions that forms the theoretical basis for the difficulty of addressing these interactions with small molecules. However, there is a small hydrophobic pocket that is critical for binding (as also confirmed by site-specific mutation studies), which might accommodate a small molecule inhibitor.

Therefore, the researchers screened approximately 7,000 purified natural products from public and proprietary libraries using an enzyme-linked immunosorbent (ELISA) assay involving release of a labeled Tcf4 binding fragment from its complex with a β-catenin fragment absorbed to an ELISA plate. Eight compounds were found that gave reproducible, concentration-dependent release of the Tcf4 fragment at less than 10 micromolar concentration. The structures and purity of these compounds (most of which are complex, multi-ringed planar compounds with multiple hydroxy groups) were then determined. The sources of these compounds include fungi, actinomycetes, and a marine sponge.

The researchers performed several additional biochemical assays to confirm the compounds’ specific disruption of the Tcf/β-catenin complex, and also performed cellular assays and an in vivo assay in the Xenopus (frog) embryo to study the activities of these compounds against β-catenin-mediated cellular effects. Each of the eight compounds shows different levels of potency in the different assays used in this study, and the compounds differ from each other in their activities in the different assays.

Two fungal-derived compounds, PKF115-854 and CGP04909, gave the best results in all the assays. It is those compounds that have been tested in preclinical studies as potential oncology drug candidates. In a study published in PNAS in 2007, researchers at the Dana-Farber and at Brigham and Women’s Hospital tested PKF115-584 in human MM cells in vitro and in xenograft models. The compound blocked expression of Wnt target genes, induced cytotoxicity in MM cells in vitro, and inhibited tumor growth and prolonged survival in the xenograft model. In a study in HCC at the Asian Liver Center at Stanford University School of Medicine, PKF115-584, CGP049090, and another of the Shivdasani group’s compounds, PKF118-310, also induced cytotoxicity in human HCC cell lines in vitro, and suppressed tumor growth and induced apoptosis in tumor cells in a human HCC xenograft model. Finally, in an abstract presented at the American Society of Hematology (ASH) meeting in December 2009, researchers at the Novartis Institute for Biomedical Research in Basel and their academic collaborators presented data that showed that CGP04090 and PKF115-584 potently inhibited the survival of primary human B-CLL cells in vitro and in vivo. In all three cases, the compounds showed no significant cytotoxicty against normal cells.

In the conclusion of the ASH meeting abstract, the authors stated that further investigations are warranted to determine the feasibility of testing these compounds in human clinical trials.

Many medicinal chemists remain skeptical about the ability of researchers to develop small-molecule drugs that target protein-protein interactions, which have satisfactory pharmacokinetics and can advance through clinical trials and reach the market. However, at least one nonpeptide small-molecule compound that targets a protein-protein interaction, the thrombopoietin receptor agonist eltrombopag (Ligand/GSK’s Promacta), has reached the market. (The FDA approved it in November 2008.) Several other small-molecule drugs that target protein-protein interactions are in clinical development. And Cambridge Healthtech Institute will be sponsoring a conference on this subject, which is scheduled for April 2010. This conference is in its third year. Thus, as also shown by the development of stapled peptides, there is renewed interest in discovering and developing drugs that address these “hard targets”.

In the 12 November issue of Nature, there was a research article and a News and Views minireview about targeting an intracellular signaling pathway with a novel type of compound called a stapled peptide.

Signaling pathways are crucial for cellular physiology, and in the pathobiology of important diseases ranging from metabolic diseases to cancer. In many cases, signaling proteins that work by binding to other proteins in protein-protein interactions are key control points in signaling pathways. However, protein-protein interactions in all but a few cases cannot be readily addressed with small molecule drugs. These targets are therefore called “undruggable”. Some signaling pathways consist entirely of these “undruggable” targets, and can only be addressed indirectly (if at all) via targeting other pathways that interact with them.

Several small-molecule drugs that do address protein-protein interactions are natural products. The best known of these is the immunosuppressant FK506 (tacrolimus, Astellas’ Prograf). This is one reason for the new interest in natural products by some companies and researchers, as we discussed in a previous blog post.

However, the 12 November Nature article, authored by James E Bradner (Chemical Biology Program, Broad Institute of Harvard and MIT, Cambridge, MA, and the Dana-Farber Cancer Institute, Boston, MA), Gregory Verdine (Department of Chemical Biology, Harvard University, Cambridge MA, and the Dana-Farber Cancer Institute), and their colleagues, takes a different approach. The researchers target specific intracellular protein-protein interactions by designing special types of peptides known as stapled peptides.

The signaling pathway that is the focus of this article is the Notch pathway. In normal physiology, this pathway regulates various aspects of cell-cell communication, cellular differentiation, cell proliferation, and cellular survival or death. Deregulated Notch pathway function is involved in diseases including cancers of the lung, ovary and pancreas, and in T-cell acute lymphoblastic leukemia (T-ALL), which is a cancer of immature T cells.

Notch is a cell-membrane receptor. Binding of one of its ligands (on the surface of an adjacent cell) to the extracellular domain of Notch triggers sequential cleavage of the Notch intracellular domain by a metalloproteinase known as TACE (tumor necrosis factor alpha converting enzyme) and by γ-secretase (an enzyme which is also involved in the amyloid pathway that is implicated in Alzheimer’s disease). The free intracellular domain of Notch, called ICN, migrates to the nucleus, and docks with the DNA-bound transcription factor CSL. The interaction between CSL and ICN creates a groove along the interface of the two proteins, which serves as a docking site for the mastermind-like protein MAML1. The resulting trimolecular complex initiates specific transcription of Notch-dependent target genes.

The binding domain of MAML1 that engages the elongated groove formed by the ICN-CSL complex is in the form of an α-helix. The researchers therefore designed a series of peptides derived from portions of the sequence of the MAML1 binding domain. These were stapled peptides in which hydrocarbon moieties are used to constrain, or “staple”, MAML1 binding-domain mimetic sequences into an α-helical conformation. One such stapled peptide, SAMH1, gave the highest affinity binding to ICN and CSL, and competitively inhibited binding of wild-type MAML1 to these proteins.

SAMH1 was cell-penetrant, and inhibited intracellular Notch pathway signaling in cultured T-ALL cell lines. Moreover, SAMH1 reduced the proliferation of a variety of T-ALL cell lines in vitro, but was inactive against T-cell tumor lines that were not dependent on the Notch pathway for their proliferation. In SAMH1-sensitive T-cell tumor lines, SAMH1 treatment activated caspases, which are involved in apoptosis. In a mouse model of T-ALL, intraperitoneally injected SAMH1 inhibited leukemic progression, and inhibited Notch pathway signaling in leukemic cells in vivo.

Stapled peptides are not conventional “drug-like” compounds. Their molecular weights are several times greater than the 500-dalton maximum prescribed by Lipinski’s rules (developed by the leading medicinal chemist Chris Lipinski), which are used to define “drug-like” properties of small molecule compounds. Moreover, peptides are usually subject to protease degradation in vivo, and thus have short serum half-lives. In most cases, peptides do not enter into cells efficiently, except for those peptides that have specific cell-membrane receptors.

However, stapled α-helical peptides, in addition to their improved binding activities to their specific targets, are protease-resistant, have improved serum half-lives, and are cell penetrant. Researchers attribute these properties to the constrained conformation of these molecules, and to the hydrocarbon staples themselves. For example, the hydrocarbon staples may confer lipophilic properties to these molecules, and thus render them membrane-penetrant.

In an earlier study, Dr. Verdine and researchers at the Dana-Farber Cancer Institute and Children’s Hospital in Boston designed a stapled α-helical peptide that initiated apoptosis by specifically binding to and activating a member of the Bcl-2 family, and that inhibited the grown of leukemic cells in a mouse model. The researchers have been continuing to develop and to determine the mechanisms of action of their Bcl-2 family-targeting stapled peptides.

The discovery-stage biotechnology company Aileron Therapeutics was founded in 2005 to develop and commercialize stapled peptides. The company’s scientific founders include Dr. Verdine, Loren Walensky (Dana-Farber Cancer Institute), and the late Stanley J. Korsmeyer (Dana-Farber Cancer Institute, a pioneer in the study of the Bcl-2 family and its role in apoptosis and in the biology of cancer). It has a pipeline of stapled peptides that it is developing for the treatment of solid and hematological tumors, the most advanced of which are in the preclinical stage. Aileron has managed to attract venture capital despite the current adverse conditions–in June 2009, the company closed a $40 million Series D financing.

Stapled peptides represent an exciting and innovative technology with the potential to address “undruggable” protein-protein interactions, and thus to treat diseases that represent major unmet medical needs. However, this technology is in an early stage, and the therapeutic value of stapled peptides has not yet been confirmed in the clinic.