Peptides are a proven drug class, with more than 40 marketed therapeutics and approximately 300 agents in clinical trials.  But despite the importance of peptide drugs, their therapeutic potential has historically been limited by poor pharmacokinetic properties resulting from in vivo proteolysis and poor cellular penetration, making it difficult for peptides to reach intracellular targets.  Our proprietary cell-permeating peptide platform enables us to chemically stabilize and improve the performance and activity of a broad range of peptides that may provide therapeutic benefit in oncology and other diseases.

Our platform is designed to generate drug-like peptides that mimic the specific helical structures found at the interface of protein -protein interactions.  These helical peptide domains act as nature’s locks and keys and enable two proteins to interact to control cellular function.  More than 3000 intracellular protein-protein interactions are facilitated by such helical peptides, and many of these protein-protein interactions involve signaling cascades such as HIF1-α, Bcl-2 or p53 that are vital to malignant transformation and cancer cell proliferation.

We stabilize peptides by synthetically manufacturing and “stapling” them with hydrocarbon bonds into their natural alpha-helical conformation. We achieve this by inserting into the peptides two or more non-natural amino acids that, when catalyzed by a chemical reaction, form a bridge to lock the peptides into a helix and maintain the biological activity of the peptide. The stabilized helical structure of our peptides creates cell-permeating therapeutic agents with large molecular surfaces for optimal target binding properties, resulting in unique drugs like ALRN-6924

We believe our platform solves many of the inherent limitations of peptides and enables us to pursue high value targets that are undruggable by existing drug technologies. Although there have been several published examples of other peptide stabilization strategies, they have not translated into clinically relevant drugs for intracellular targets. Our all-hydrocarbon staple, or linker, has emerged as a solution that improves protease resistance, enables cellular penetrance and maintains biological activity.  And because our cell-permeable peptides are larger in size than typical small molecule drugs, they can better interface with the broad, shallow binding pockets of these critical intracellular protein-protein interactions.


Peptides are functional subunits of proteins that act as nature’s locks and keys and enable two proteins to interact to control cellular function.


The alpha-helical structure is the most common peptide structure found at these protein interfaces.


Because peptides lose their shape by unwinding when removed from their natural protein scaffold, their chemical stability and activity is greatly reduced.


At Aileron, we stabilize peptides by “stapling” them with hydrocarbon bonds into their natural alpha-helical conformation.


Unlike large proteins, such as monoclonal antibodies or other naturally occurring proteins, that do not penetrate cell membranes due to their size and biophysical properties, stabilized alpha-helical peptides can in many circumstances penetrate cells and still maintain high affinity to their large protein surface targets. Our cell-permeating peptides typically retain the molecular target specificity of their underlying native protein structure.


Over 3,000 known protein-protein interactions are mediated by a helical peptide interface; our data and a growing body of third-party publications support the utility of cell-permeating peptides against a wide variety of targets.

We believe that our cell-permeating peptide chemical strategy may allow us to improve on many of the intrinsic limitations of peptides and to develop molecules that interact with high value targets that may not be amenable to small molecules or monoclonal antibodies.

The p53 protein plays a central role in the mechanisms that defend the human body from cancer, including regulation of cell division and progression through the cell cycle, programmed death of cancerous cells (or “apoptosis”), and inducing the immune system to respond against cancer cells.

When DNA damage is detected in a cell (for example, following UV radiation), p53 activates genes that interrupt the cell cycle to ensure that damaged cells do not grow and propagate uncontrollably, leading to cancer. Functional p53 is therefore critical to human health, earning it the title of  the “guardian of the genome.” When p53 itself is mutated or pathologically inhibited by its natural regulators, cells grow uncontrollably and may eventually form a cancerous tumor. Approximately half of all cancer patients at initial diagnosis have cancers that circumvent the p53 mechanism by deactivating mutations in p53 itself, commonly referred to as mutant p53.  In the remaining cancer patients, the p53 mechanism is circumvented by activating or overexpressing the natural suppressor proteins of p53, including MDM2 and MDMX, making them an ideal target for novel cancer therapies.

Approximately half of all cancer patients at initial diagnosis have cancers that circumvent the p53 mechanism by deactivating mutations in p53 itself, commonly referred to as mutant p53. 

MDM2 is the primary regulator of p53, which acts by shuttling p53 out of the nucleus and targeting it for degradation. MDMX, which generally acts to sequester p53, is most abundantly expressed in normal bone marrow cells.  In the event of DNA damage, these two suppressor proteins detach from p53 so that it is activated to respond to DNA damage.

Low levels of p53 induce cell cycle arrest, which is the basis for the cell to repair DNA damage.  High levels of p53 can, under certain circumstances, trigger apoptosis, a form of programmed cell death.  This is one of the body’s natural defense mechanisms against cancer and for dealing with DNA damage. However, activation and overexpression of MDM2 and MDMX are found in a significant number of cancers that commonly present with Wild Type p53. In these cancers, cancer cells co-opt and over-activate some of the mechanisms used by normal cells to restrain p53 function, thereby nullifying the tumor suppression capabilities of Wild Type p53. In this environment, the cancer cell growth is left unchecked.


ALRN-6924 is a first-in-class, stabilized cell-permeating alpha-helical peptide that mimics the p53 tumor suppressor protein to disrupt its interactions with both its endogenous inhibitors, MDMX and MDM2. ALRN-6924 represents the proof-of-concept for Aileron’s peptide platform, and we continue to evaluate ALRN-6924’s unique  features. For example, we recently presented at the 24th Congress of the European Hematology Association characterizing ALRN-6924’s differentiated hematological safety profile vs. MDM2-only inhibitors. ALRN-6924 binds to both MDMX and MDM2 with nanomolar affinities and demonstrates evidence of specific on-target engagement in vitro by gene expression profiling and its p53-dependent effects on cancer cell lines, with activity against nearly all wild type p53 cell lines studied and no discernible effect in almost all mutant p53 cell lines. In in vivo studies, ALRN-6924 shows p53-dependent cell cycle arrest, apoptosis and anti-tumor activity in mouse xenograft models of cancer with clear correlation to on-target PK and pharmacodynamic activity.

Cell-permeating Peptides for Targeted Protein Degradation  

Aileron is developing a new class of targeted protein degradation reagents leveraging our stabilized, cell-permeating peptide platform. Targeted protein degradation is an emerging drug discovery approach that uses compounds capable of binding two distinct proteins, a target protein and a second ubiquitinating enzyme, to tag the target protein for degradation in the cell.  This approach, which is also known as protease-targeting chimeras, or “PROTACs”, has advantages over traditional inhibitor-based drug strategies, since the target protein is completely degraded, not just transiently inhibited. Our peptide-based degraders are based on MDM2-binding peptides like ALRN-6924 that are covalently coupled to “bait” moieties to recruit target proteins to the vicinity of MDM2, which in turn tags (i.e., ubiquitinates) the target protein for degradation in the proteasome. Our unique strategy can realize the following critical advantages vs. small molecule-based agents in this emerging field:

  • High affinity, slow dissociation interactions with the ubiquitin ligase MDM2, which is present in all cells;

  • Activation of p53, which stimulates higher expression of MDM2. Our degraders “make their own” ubiquitin ligase enzymes in p53-Wild Type cells;

  • Concurrent activation of p53, which is synergistic with degradation of other tumor-promoting proteins (for example, AR, EGFR, BRD4, Myc…);

  • As a class, and as demonstrated in the clinical with ALRN-6924, peptide-based agents tend to have fewer off-target effects than small molecules;

  • Targeted protein degradation agents based on ALRN-6924 can leverage a substantial patient safety and efficacy database of the “enzyme half” of the drug to show a well-tolerated safety profile with single agent activity and multiple complete and partial remissions in several tumor types.



Hypoxia-inducible transcription factors (HIF) are key regulators of cellular adaptation to hypoxia in solid tumors, and HIF-1α controls the expression of genes involved in anaerobic metabolism, angiogenesis, cell growth and survival. We are developing novel inhibitors of HIF-1α that mimic the structure and function of the CITED2 protein, an endogenous negative regulator of the interaction between HIF-1α and p300 proteins, by designing a stabilized, cell-permeating peptide derived from CITED2.  Our first example of a potent and selective inhibitor of HIF-1α-dependent transcription is a peptide we call ATSP- 9172, which binds to the CH1 domain of p300 and disrupts the HIF-1α C-TAD/CH1 interaction in biochemical assays and inhibits HIF-dependent reporter gene activity in cells. Examination of endogenous transcript levels these cells revealed that ATSP-9172 down-regulates the transcription of HIF-1α target genes, such as adolase C, angiopoietin-like 4, and carbonic anhydrase 9 in a dose-dependent manner but does not affect the expression of non-HIF target genes, verifying a specific and on-target mechanism of action. ATSP-9172 exhibits a dramatic improvement in solubility and plasma stability profile relative to the linear peptide and demonstrates favorable pharmacokinetic properties in mice by providing high systemic exposure, low plasma clearance and long elimination half-life. Finally, intravenous administration of ATSP-9172 significantly inhibits tumor growth in a PC-3 human prostate tumor xenograft model.  Our results demonstrate that a stapled peptide mimicking the HIF inhibitory function of the native CITED2 protein provides a novel and specific strategy to suppress HIF-1 α-dependent gene expression for cancer therapy.

BCL-2 Family

While selective targeting of BCL-2 with Venetoclax has emerged as a successful therapy in hematologic cancers, the BCL2-family member MCL-1 is an oncogenic driver in almost every subtype of solid tumors and heme malignancies.  In addition, MCL-1 upregulation and BCL-2 mutational escape has emerged as a cause of venetoclax treatment failure. These escape mutants remain susceptible to BIM peptide binding.  Aileron is developing first-in-class BCL-2-family pan-inhibitor peptides to uniquely target MCL-1 and combinations of BCL-2 family proteins and overcome BCL-2 mutational escape for solid tumors (e.g. small-cell lung & triple-negative breast cancers) and heme cancer.  We have generated peptides with potent binding profiles for BCL-2-family members and shown antiproliferative activity in cell lines by translating our design concepts from ALRN-6924/p53 to BIM (e.g., choice/position of the staple, charge state and distribution, hydrophobicity and amphipathicity, etc.). We’ve advanced from the original academic stapled BH3 peptides to compounds with drug-like pharmacology, and we’ve developed unique structure-activity relationships to achieve on-target cellular activity for binding to the Bcl-2 family of proteins.






Macrocyclic Peptides as PPI inhibitors

Reactivating p53 Tumor Suppressor