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 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.
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:
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.