Degraders for Rare, Undruggable, Cancers – Two Natural Cap

DT2216 was engineered to dodge one of oncology's oldest problems: Bcl-xL inhibitors kill platelets along with cancer cells.

By recruiting VHL, an E3 ligase that platelets barely express, the drug was supposed to degrade Bcl-xL everywhere except where it causes thrombocytopenia. Instead, according to the report, its fibrolamellar carcinoma (FLC) trial combining DT2216 with irinotecan is currently suspended because of unacceptable toxicity. Two Natural Capital, whose report does not disclose a trading position, uses the setback to lay out a broader case for protein degraders, including an unapproved preclinical bioPROTAC, as a way around the safety limits that have kept conventional kinase inhibitors out of FLC.

Ticker: Not applicable. No public ticker is identified for the report's primary subject (Dialectic Therapeutics, privately referenced).
Research Firm: Two Natural Capital
Report URL: https://www.twonaturalcap.com/p/degraders-for-rare-undruggable-cancers?ref=shortreport.fyi
Report date: 2026-10-28
Position Disclosure: Not disclosed in the source report.

Thesis

Two Natural Capital's report argues that FLC's genetic driver is biologically undruggable by conventional means, and that degrader technology, not classic inhibition, is the more plausible path to a safe therapy.

• Fusion Driver, No Safe Target: FLC is typically caused by a roughly 400kb deletion on chromosome 19 that fuses DNAJB1 and PRKACA; directly inhibiting the fusion is said to be unworkable because PRKACA is part of essential wild-type protein kinase A, and shutting it down causes unacceptable side effects.
• Platelet-Sparing Design Meets Real-World Toxicity: DT2216 binds Bcl-xL and VHL, a ligase with low platelet expression, specifically to avoid the thrombocytopenia that limits conventional Bcl-xL inhibitors, but Dialectic Therapeutics' FLC trial pairing DT2216 with irinotecan is currently suspended due to unacceptable toxicity.
• Lysine-Driven Selectivity: A preclinical SPOP-based bioPROTAC binds both the DNAJB1::PRKACA fusion and normal PRKACA, but the fusion's DNAJB1 segment reportedly carries accessible lysines that make it a more attractive substrate for ubiquitination and degradation.
• Tissue-Selective Ligase Toolkit: Kymera Therapeutics' S-1 filing describes an "E3 Ligase Whole-Body Atlas" and cites identification of a "novel bone marrow sparing E3 ligase," offered as evidence that matching ligase to tissue could systematically improve degrader safety.
• Catalytic Low-Dose Mechanism: Because one degrader molecule can act on multiple copies of its target rather than simply occupying it, the report argues lower doses might limit residual off-target toxicity, both Bcl-xL inhibition in megakaryocytes for DT2216 and wild-type PRKACA inhibition for the bioPROTAC.
• Screen Origin: The DT2216-in-FLC rationale traces to Dr. Sanford Simon of Rockefeller University, who screened more than 5,000 compounds against FLC tumor lines and flagged irinotecan and Bcl-xL inhibitors as active hits.
• Weak Baseline of Care: Surgery is described as the only generally effective FLC treatment, with chemotherapy and standard immunotherapy called "fairly ineffective" against tumors with low mutational burden and low PD-L1 expression; five-year survival is cited at roughly 40%.

Catalysts

• Trial resumption watch: Resumption of Dialectic Therapeutics' suspended DT2216 FLC trial, pending resolution of the reported toxicity issue (no date given), would signal whether the platelet-sparing design can be salvaged clinically.
• Cross-indication safety read-through: Additional DT2216 data from the FLC/irinotecan and platinum-resistant ovarian cancer/paclitaxel studies (no date given) would show whether the toxicity problem is FLC-specific or broader.
• Fusion-site discovery progress: Progress from Fibrolamellar Cancer Foundation-funded work on a selective DNAJB1::PRKACA binding site (ongoing, no date given) would test the circumstantial case for fusion-specific targeting.
• bioPROTAC clinical transition: Advancement of the SPOP-based FLC bioPROTAC toward clinical testing would be a notable inflection, as the report notes no bioPROTAC has yet entered clinical trials.
• Tissue-ligase validation: Further validation of tissue-selective E3 ligases, including the bone-marrow-sparing ligase described in Kymera's S-1 (ongoing), would broaden support for the tissue-selection thesis beyond FLC.

Company Response

The report does not indicate that Dialectic Therapeutics, Kymera Therapeutics, or any other company named was contacted for comment, and no company responses are cited in the source report.

Notable Details

• FLC patients are typically diagnosed as adolescents or young adults, yet five-year survival is cited at only around 40%.
• A Johns Hopkins team is developing a vaccine targeting the DNAJ-PKAc fusion that, unlike Moderna's personalized melanoma vaccine work, reportedly would not need to be customized patient by patient.
• In Dr. Simon's 5,000-plus compound screen, irinotecan emerged as a promising hit even though topoisomerase I inhibitors are typically more useful against fast-growing cancers, and FLC is relatively slow-growing.
• Standard immunotherapy is described as a poor fit for FLC because its tumors tend to have low mutational burden, intact mismatch repair, and low PD-L1 expression; the report calls this the opposite of the profile expected to respond well to Keytruda.

"This is a pretty fascinating application of degraders, whereby selectivity is achieved based on how compelling a protein's structure is to the proteasome."

Two Natural Capital uses this line to describe the bioPROTAC strategy, in which the FLC fusion protein may be preferentially destroyed because its extra accessible lysines make it a better substrate for ubiquitination.

FAQs

What is Dialectic Therapeutics' DT2216 and why does it matter for FLC?

DT2216 is a degrader drug that binds both Bcl-xL and the E3 ligase VHL, designed to kill Bcl-xL-dependent cancer cells while sparing platelets, which express little VHL. It is being studied in FLC combined with irinotecan and in platinum-resistant ovarian cancer combined with paclitaxel; the report states the FLC trial is currently suspended due to unacceptable toxicity.

What does Two Natural Capital's report argue about degraders in rare cancers?

The report argues that fibrolamellar carcinoma's DNAJB1::PRKACA fusion cannot be safely hit with conventional kinase inhibitors because doing so also disables essential wild-type protein kinase A. It presents degrader technology, including DT2216 and a preclinical bioPROTAC, as a potential way to achieve selectivity that active-site inhibitors cannot.

What is Kymera Therapeutics' role in this report, and does it have a stock ticker?

Kymera Therapeutics is cited as a comparator company whose S-1 filing describes an "E3 Ligase Whole-Body Atlas" used to find ligases with differentiated tissue expression, including a "novel bone marrow sparing E3 ligase." The source report does not provide Kymera's trading ticker.

What causes fibrolamellar carcinoma?

Per the report, most FLC cases arise from a roughly 400-kilobase deletion on chromosome 19 that fuses the DNAJB1 and PRKACA genes into a single fusion protein. This fusion is described as the central driver of the disease, which most often affects adolescents and young adults.

Why can't doctors just use a kinase inhibitor to block the FLC fusion protein directly?

Because PRKACA, part of the fusion, also encodes a component of normal protein kinase A, which is essential for healthy cell function elsewhere in the body. The report states that inhibiting this activity directly causes unacceptable side effects, which is why the author frames FLC as a target requiring a different drug mechanism entirely.

What is a bioPROTAC, and has one been tested in FLC patients?

A bioPROTAC is described as a fusion protein that combines a protein-of-interest binding component with part of an E3 ligase, rather than relying on a small molecule to bridge the two, as conventional PROTACs do. The report states that no bioPROTAC has yet entered clinical trials, including the SPOP-based construct designed for FLC, which remains preclinical.

Why is DT2216's FLC trial suspended despite its platelet-sparing design?

The report states the trial combining DT2216 with irinotecan is currently suspended because of unacceptable toxicity, without specifying the exact nature of that toxicity. This is notable because DT2216 was specifically engineered around VHL's low platelet expression to avoid the thrombocytopenia typically seen with Bcl-xL inhibitors.

Are there other treatment approaches being developed for FLC besides degraders?

Yes. The report cites a Johns Hopkins team developing a vaccine against the DNAJ-PKAc fusion protein that, unlike Moderna's personalized melanoma vaccine approach, would not require customization for each patient since the same fusion drives most FLC cases. It also notes the Fibrolamellar Cancer Foundation is funding separate research into a selective fusion-targeting binding site.

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