How Peptide Therapeutics Are Tackling "Undruggable" Targets
A new class of precision medicines is challenging one of oncology's most stubborn barriers – opening doors to treatments once thought impossible.
Imagine a fortress protected by intricate locks that no existing key can open. For decades, this has been the challenge facing cancer researchers trying to target critical proteins driving tumor growth. Traditional drug discovery has struggled to disrupt these tightly bound protein complexes, leaving many high-mortality cancers with limited treatment options. At the 2020 AACR Virtual Annual Meeting II, Sapience Therapeutics presented preclinical data on two innovative peptide programs demonstrating promising approaches to this fundamental problem 1 .
For years, cancer research has faced a significant limitation: while scientists have identified numerous proteins that drive cancer progression, many of these have been considered "undruggable" – meaning they cannot be effectively targeted with conventional small-molecule drugs or antibodies 1 .
Many oncogenic proteins perform their destructive work through protein-protein interactions (PPIs) that occur deep inside cells, with interfaces that are large, flat, and lacking obvious pockets for small molecules to bind.
Transcription factors – proteins that control the expression of genes critical to cancer growth – have been particularly challenging to target with traditional approaches 1 .
Sapience Therapeutics has focused on developing peptide-based therapeutics specifically designed to overcome this challenge. Their platform enables the discovery of peptides capable of disrupting intracellular PPIs, potentially unlocking targets previously considered beyond the reach of drug therapy 1 .
At the core of Sapience's approach is their proprietary SPEAR™ platform, which enables the development of peptide therapeutics that can act inside cancer cells 2 . Unlike conventional small molecules or antibodies, these peptides are engineered to be both small enough to enter cells and precise enough to disrupt specific protein-protein interactions that drive cancer progression.
They are designed to mimic key regions of proteins involved in these destructive interactions, essentially serving as "decoys" that prevent the oncogenic proteins from binding to their natural partners and activating cancer-promoting pathways 1 .
Peptides offer greater specificity than small molecules, potentially reducing off-target effects.
They can target intracellular interactions that antibodies cannot reach since antibodies are generally too large to cross cell membranes.
One of the lead programs presented at the AACR meeting was ST101 (now known as lucicebtide), a first-in-class antagonist of the transcription factor C/EBPβ 1 2 .
C/EBPβ plays a critical role in regulating genes involved in cell proliferation, survival, and differentiation. In many cancers, this regulatory pathway becomes hijacked, promoting tumor growth and survival. ST101 was designed to specifically block the harmful functions of C/EBPβ while preserving its normal physiological activities 1 .
The preclinical data presented demonstrated that ST101 effectively attenuates oncogenic gene transactivation in cancer cells, leading to significant antitumor activity 1 . By disrupting specific protein-protein interactions involving C/EBPβ, the peptide prevents this transcription factor from activating genes that drive cancer progression.
Research has shown that C/EBPβ is involved in multiple cancer types, including breast cancer, prostate cancer, melanoma, and glioblastoma 2 . The broad involvement of this transcription factor in various cancers suggests that an effective antagonist could have wide-ranging applications in oncology.
Breast Cancer
Prostate Cancer
Melanoma
Glioblastoma
The second program featured in the AACR presentations targeted β-catenin, a protein that serves as the central effector of the Wnt signaling pathway 1 . This pathway is fundamental to cell growth and differentiation, but when dysregulated, it becomes a powerful driver of many cancers.
In the Wnt pathway, β-catenin accumulates in the cell and travels to the nucleus, where it activates genes promoting cell proliferation and survival. In many cancers, including breast cancer, colorectal cancer, and others, mutations in this pathway lead to uncontrolled accumulation of β-catenin, making it a prime therapeutic target 1 .
Sapience's β-catenin antagonist peptide (now designated ST316) demonstrated promising results in breast cancer models, showing an ability to attenuate oncogenic gene transactivation and promote antitumor activity 1 . The preclinical data presented at AACR provided evidence that this peptide could effectively disrupt β-catenin's cancer-promoting functions.
The development of these peptide therapeutics required specialized reagents and methodologies to target intracellular protein-protein interactions effectively. The table below outlines key components of the research toolkit used in these programs:
| Research Tool | Function/Application | Significance in Drug Development |
|---|---|---|
| Peptide Libraries | Screening for optimal binding sequences | Foundation for identifying lead compounds that effectively disrupt specific PPIs |
| Cancer Cell Lines | In vitro testing of compound efficacy | Enable evaluation of antitumor activity across different cancer types |
| Animal Tumor Models | In vivo assessment of antitumor effects | Provide critical data on pharmacokinetics, toxicity, and efficacy before human trials |
| Biomarker Assays | Measurement of target engagement and pathway modulation | Help establish proof-of-concept and guide patient selection strategies |
The path from identifying a target to developing a therapeutic candidate involves multiple carefully designed stages. For both ST101 and the β-catenin antagonist program (ST316), Sapience followed a systematic approach:
Researchers first identified C/EBPβ and β-catenin as promising targets based on their well-established roles in cancer pathways and the documented challenges in targeting them with conventional approaches 1 . The rationale was that effective inhibitors of these targets could address significant unmet needs in oncology.
Using their SPEAR platform, scientists designed peptides capable of disrupting the specific protein-protein interactions that enable these transcription factors to drive cancer progression 1 . This involved structural biology approaches to identify key interaction domains and computational modeling to guide peptide design.
The lead candidates underwent extensive testing in cancer cell lines to evaluate their effects on gene expression, cell proliferation, and apoptosis (programmed cell death) 1 . Researchers employed various assays to measure the peptides' ability to engage their intended targets and modulate downstream signaling pathways.
The most promising candidates advanced to animal studies, primarily using mouse models of human cancers 1 . These experiments provided critical data on the compounds' pharmacokinetics (how the body processes the drug) and pharmacodynamics (the drug's effects on the body), as well as preliminary safety information.
| Parameter | ST101 (C/EBPβ Antagonist) | β-catenin Antagonist (ST316) |
|---|---|---|
| Mechanism of Action | Antagonizes C/EBPβ-mediated transcription | Disrupts β-catenin protein-protein interactions |
| Primary Readout | Attenuation of oncogenic gene transactivation | Attenuation of oncogenic gene transactivation |
| Experimental Models | Various cancer cell lines | Breast cancer models |
| Reported Outcome | Drives antitumor activity | Promotes antitumor activity |
| Development Status (2020) | Preclinical | Preclinical |
The presentations at AACR 2020 came at a pivotal time for cancer research. The meeting itself, held virtually due to the COVID-19 pandemic, attracted over 61,000 attendees and featured discussions on the latest advances in cancer science 3 . In this context, Sapience's data on novel approaches to targeting traditionally elusive oncogenic proteins represented exactly the type of innovative science that the meeting was designed to highlight.
The implications of successfully targeting transcription factors like C/EBPβ and β-catenin extend across multiple cancer types. Transcription factors sit at the convergence points of many signaling pathways, making them potentially powerful leverage points for therapy. Effective targeting of these proteins could provide new treatment options for patients with cancers that are currently difficult to treat.
| Program | 2020 Status | Current Status (2025) | Key Milestones Achieved |
|---|---|---|---|
| ST101 (Lucicebtide) | Preclinical | Phase 2 trials in multiple indications 2 | Orphan Drug Designation for melanoma and glioblastoma; Fast Track Designation for recurrent GBM 2 |
| β-catenin Antagonist (ST316) | Preclinical | Phase 2 trials in colorectal cancer 2 | Orphan Drug Designation for Familial Adenomatous Polyposis; Phase 1 dose escalation completed 2 |
Phase 2 Clinical Trials
Phase 2 Clinical Trials
The research presented by Sapience Therapeutics at the 2020 AACR Virtual Annual Meeting II represents more than just early data on two drug candidates – it exemplifies a growing frontier in cancer research focused on expanding the druggable genome. By developing innovative peptide-based approaches to target transcription factors and other intracellular proteins, researchers are challenging long-standing limitations in drug development.
The progression of both ST101 (now lucicebtide) and ST316 from preclinical programs in 2020 to ongoing Phase 2 clinical trials in 2025 demonstrates the viability of this approach 2 . As these programs continue to advance, they offer hope for new treatment options for patients with cancers that currently have limited therapeutic alternatives.
Perhaps more importantly, the success of these platforms could pave the way for targeting other currently "undruggable" proteins, potentially opening new avenues for treating not just cancer but other diseases as well. As these technologies mature, we may be witnessing the early stages of a fundamental shift in how we approach drug development – one that could ultimately make currently untreatable diseases manageable or even curable.