The AACR Annual Meeting is widely regarded as one of the world’s most influential cancer conferences, offering an early glimpse into the future direction of cancer research and oncology drug development each year. AACR 2026 featured numerous cutting-edge studies across fields such as precision oncology, antibody-drug conjugates (ADCs), immuno-oncology, ctDNA, and perioperative treatment strategies. Among them, however, the “New Drugs on the Horizon” session stood out as one of the most compelling programs of the meeting.

Organized by the AACR Chemistry in Cancer Research Working Group, this flagship translational research session is significant not merely because it presents study results, but because it provides an early look at which emerging biological concepts may ultimately evolve into real therapeutic targets.

In particular, the session is notable for unveiling the mechanisms and structural concepts of innovative platforms that are still in very early stages of development, ranging from preclinical research to early clinical trials. As such, it serves as a preview of the future landscape of anticancer drug development. In fact, while only around eight compounds across two sessions were introduced just three years ago, the program expanded significantly in 2025 to three sessions featuring a total of twelve compounds, reflecting its rapidly growing importance.

Another striking trend is the shift in participation. Whereas the session previously consisted mainly of exploratory presentations from venture biotech companies, it has increasingly become a stage where global pharmaceutical companies and leading biotech firms competitively unveil their next-generation innovation platforms.

This evolution highlights how the center of competition in oncology drug development is moving away from simple clinical development capabilities toward the ability to define novel cancer biology first and successfully translate it into therapeutics. In this article, I would like to focus particularly on the protein degradation-based platforms that attracted considerable attention during this year’s session.

Figure. Protein degradation-based drug candidates presented at AACR 2026 “New Drugs on the Horizon” (Source: ChatGPT & Hanlim Moon).

At this year’s AACR meeting, targeted protein degradation platforms drew major attention as a strategy to overcome both resistance to conventional targeted therapies and the limitations of “undruggable” targets. In particular, molecular glue degraders represent a fundamentally different approach from traditional inhibitors because they induce the degradation of proteins themselves by creating novel interactions between E3 ligases and target proteins.

This strategy expands therapeutic possibilities beyond conventional targets to previously difficult-to-drug entities such as transcription factors, structural proteins, and protein complexes. Indeed, the recent FDA approval of the estrogen receptor degrader vepdegestrant (Veppanu) symbolically demonstrated that protein degradation technology is no longer merely an experimental concept, but is now entering the realm of clinically validated therapeutic platforms.

Most strikingly, five of the twelve compounds introduced during this year’s “New Drugs on the Horizon” session were based on protein degradation technologies.

One of the most impressive platforms presented at AACR 2026 was EPI-326 from EpiBiologics. EPI-326 is a bispecific EGFR-degrading antibody that simultaneously recognizes EGFR and ITGB6. Importantly, it introduced a novel concept of a “tumor-selective receptor elimination platform,” rather than functioning simply as a conventional EGFR inhibitor.

Traditional EGFR therapies have long faced structural limitations, including repeated resistance and toxicity in normal tissues. The key innovation of EPI-326 lies in its utilization of ITGB6, which is selectively overexpressed in tumors, as a tumor-specific co-expression marker to expand the therapeutic window.

The platform is designed to selectively induce EGFR internalization and degradation within the tumor microenvironment, thereby eliminating EGFR itself and blocking residual signaling scaffolds. At the same time, it aims to minimize EGFR-related toxicity in normal tissues. This represents a sophisticated biological engineering strategy centered on selective receptor removal.

Particularly noteworthy was how the platform integrated antibody engineering, tumor-specific dual targeting, receptor trafficking control, and targeted protein degradation biology into a single therapeutic technology. This may represent a paradigm shift in which antibody therapeutics evolve beyond simple neutralizing antibodies toward selectively eliminating receptors directly within cancer cells.

Tango Therapeutics’ TNG961 was another highly innovative platform highlighted during the AACR 2026 “New Drugs on the Horizon” session. The compound is a synthetic lethality-based molecular glue degrader designed to exploit HBS1L dependency in FOCAD-deficient cancer cells.

Recent studies suggest that FOCAD functions as a tumor suppressor involved in maintaining ribosomal stability and normal protein translation processes. In several cancer types, FOCAD loss or reduced expression has been repeatedly observed, leading to instability in protein translation and increased translational stress within cancer cells.

As a consequence, abnormal stalled ribosomes and damaged translation complexes accumulate, forcing cancer cells to become increasingly dependent on ribosome rescue pathways that recover stalled ribosomes and restore translation processes.

HBS1L is one of the key proteins in this rescue pathway, resulting in enhanced HBS1L dependency in FOCAD-deficient tumors. TNG961 specifically exploits this vulnerability. By using molecular glue-mediated protein degradation to eliminate HBS1L itself, the drug aims to collapse the ribosome rescue machinery on which cancer cells rely, ultimately inducing catastrophic translational failure and antitumor activity.

This strategy is significant because it extends therapeutic intervention beyond traditional signaling pathways into entirely new areas involving ribosome biology and proteostasis.

Neomorph’s NEO-811 was perhaps one of the most symbolic examples of the future direction of targeted protein degradation technologies presented during the AACR 2026 “New Drugs on the Horizon” session.

NEO-811 is a molecular glue degrader targeting ARNT (HIF-1β), a critical regulator of hypoxia signaling in renal cell carcinoma, particularly clear cell renal cell carcinoma.

ARNT acts as an essential binding partner for HIF-1α and HIF-2α, enabling transcriptional activation of genes involved in key cancer biological processes such as hypoxia adaptation, angiogenesis, and metabolic reprogramming.

In renal cell carcinoma, where VHL loss is common, HIF signaling remains constitutively activated. In this context, NEO-811 presents a particularly intriguing approach because it seeks to disrupt the HIF transcriptional complex at a higher hierarchical level than existing HIF-2α inhibitors such as belzutifan (Welireg).

Previously, transcription factors like ARNT were considered difficult-to-drug targets because they lack enzymatic active sites suitable for conventional small molecules. However, NEO-811 utilizes molecular glue degradation technology to create novel interactions between E3 ligases and ARNT, thereby inducing degradation of the target protein itself.

The presentation demonstrated potent ARNT degradation, suppression of hypoxia-related transcriptional programs, and meaningful antitumor activity. This represents a powerful example of how protein degradation technologies may expand therapeutic opportunities toward transcription factors once considered “undruggable.”

Overall, the AACR 2026 “New Drugs on the Horizon” session clearly demonstrated that targeted protein degradation technologies are no longer simply an experimental drug development strategy, but are rapidly emerging as a major pillar of future oncology therapeutics.

Importantly, the compounds presented this year sought to expand therapeutic intervention into areas previously considered inaccessible, including transcription factors, ribosome regulatory proteins, and receptor complexes. Moreover, rather than merely inhibiting protein function, these approaches aim to eliminate proteins themselves, thereby directly collapsing fundamental survival systems in cancer cells such as transcriptional regulation, stress adaptation, and protein homeostasis.

At the same time, these technologies also face important challenges, since they directly manipulate biological systems that play essential roles in normal cells. Issues such as therapeutic window optimization, resistance mechanisms, and predictive biomarker development remain critical hurdles.

Ultimately, the future success of targeted protein degradation technologies will likely depend on how selectively and safely they can modulate the complex biology underlying cancer.