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  "id": "228",
  "slug": "undruggable-thins",
  "edition": "2026-10-18T00",
  "url": "https://hangingcontext.com/stories/2026-10-18/undruggable-thins/",
  "newsroom": "health-biotech",
  "beat": null,
  "newsroom_title": "Health & Biotech",
  "angle": "The 'undruggable' pitch thins: designed MYC binders depleted tumor cells in mice; bivalent and macrocyclic hits landed on BPTF and HDAC6.",
  "headline": "MYC, BPTF, HDAC6: The 'Undruggable' List Keeps Shrinking",
  "dek": "Three bioRxiv preprints posted October 16 attack three historically hard targets — designed proteins that deplete MYC-driven tumor cells in mice, a bivalent inhibitor for the BPTF reader, and a high-resolution macrocycle structure for HDAC6.",
  "published_at": "2026-10-18T01:20:36Z",
  "labels": {
    "trust": "reported",
    "trust_text": "Reported · 3 sources",
    "newsroom": "Health & Biotech"
  },
  "source_count": 3,
  "publishers": [
    "biorxiv-protein-structure-drug-discovery"
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  "key_facts": [
    {
      "text": "De novo designed proteins bind the MYC oncoprotein with nanomolar affinity, in a preprint.",
      "self_reported": true,
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    {
      "text": "The designed binders disrupt MYC-MAX interactions and remodel MYC-associated protein complexes.",
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      "text": "In orthotopic pancreatic cancer models in mice, binder-expressing tumor cells were selectively depleted.",
      "self_reported": true,
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    {
      "text": "MJ-1, a bivalent peptide–small molecule conjugate, inhibits both the PHD and bromodomain reader modules of BPTF by exploiting a ligand-induced conformational change.",
      "self_reported": true,
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    {
      "text": "A 1.9 Å crystal structure shows a macrocyclic nonapeptide inhibiting HDAC6 CD2 with nanomolar potency, coordinating zinc through a noncanonical thiolate-containing amino acid.",
      "self_reported": true,
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  "sections": [
    {
      "heading": "MYC finally has binders",
      "paragraphs": [
        {
          "markdown": "In a bioRxiv preprint posted October 16, McNamara-Bordewick and colleagues — with David Baker among the authors — report de novo designed proteins that bind the MYC oncoprotein with nanomolar affinity. The designed binders disrupt MYC-MAX interactions and remodel MYC-associated protein complexes. Binder expression decreased cell proliferation across diverse MYC-dependent tumor models — hematopoietic, liver, and pancreatic — and in orthotopic pancreatic cancer models in mice, binder-expressing tumor cells were selectively depleted.",
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    },
    {
      "heading": "BPTF gets a bivalent",
      "paragraphs": [
        {
          "markdown": "A second preprint attacks an epigenetic reader protein. The BPTF PHD-bromodomain cassette specifically recognizes the H3K4me3K14ac histone modification, and ligand binding induces a conformational change between the PHD and bromodomain modules. The authors designed MJ-1, a bivalent peptide–small molecule conjugate that inhibits both reader domains by exploiting that ligand-induced rearrangement. The new part of this story, offered as reasoning: instead of inhibiting one reader domain, MJ-1 engages both at once by exploiting the rearrangement.",
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    },
    {
      "heading": "HDAC6 gets a picture",
      "paragraphs": [
        {
          "markdown": "The third preprint supplies atomic detail: a 1.9 Å crystal structure of the HDAC6 CD2 domain bound to macrocyclic nonapeptide 1, which inhibits HDAC6 with nanomolar potency. The structure shows zinc coordination by a noncanonical thiolate-containing amino acid and a network of direct and water-mediated hydrogen bonds that matches previously reported tetrapeptide and octapeptide macrocycles — a shared structural scaffold, now with a high-resolution picture to design against.",
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    },
    {
      "heading": "What thins is the pitch, not the work",
      "paragraphs": [
        {
          "markdown": "Step back and the week looks coordinated even though it is not. Three different hard-target classes — the MYC transcription factor, a dynamic tandem epigenetic reader, a histone deacetylase — each fell to a different modality: a de novo designed protein, a bivalent peptide–small molecule conjugate, and a macrocyclic peptide solved at 1.9 Å. The common thread is that none of the three is a conventional small molecule doing the conventional thing. MYC was bound by something built for it from scratch; BPTF was gripped at two domains at once; HDAC6 was inhibited by a macrocycle whose zinc-coordination chemistry a medicinal chemist would not have drawn on a whiteboard. The undruggable label, in each case, described the limits of one modality, not of the target.",
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              "manifest_id": "1792232006426784323",
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        {
          "markdown": "The reasoning a VC should take from the trio: undruggable is increasingly a statement about modality imagination rather than chemistry. De novo binders, bivalent conjugates, and macrocycles each cracked something a conventional small molecule could not — but none of this is a drug yet. All three are preprints with no clinical validation: the MYC work is in mouse and cell models, the BPTF paper reports no in vivo efficacy data, and the HDAC6 paper is a structure. The diligence question shifts from whether anyone can bind the target to whether the modality can reach it, selectively, in a patient — a harder and more expensive question, and exactly the one worth underwriting.",
          "cites": [
            {
              "manifest_id": "1792232006426336673",
              "claim_ids": [
                "1792233758183873711"
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            {
              "manifest_id": "1792232006426784323",
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        },
        {
          "markdown": "For diligence, the practical screen this suggests: when a pitch deck says undruggable, ask which modalities have actually been tried. If the answer is small molecules, the target may be undrugged rather than undruggable — these three preprints are the exhibit. Then ask the harder questions these papers leave open: delivery, selectivity across protein families, and safety in animals. The MYC binders were expressed in the tumor cells rather than delivered as drugs; the BPTF conjugate has no animal data; the HDAC6 structure is a picture, not a pharmacokinetic profile. The alpha is in the modality; the risk is in everything after binding.",
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  ],
  "unresolved": [
    "Whether the de novo MYC binders can be delivered to tumors in animals as proteins rather than expressed genetically — the preprint demonstrates efficacy through binder expression.",
    "Long-term safety and off-target effects of the MYC binders in vivo, which the preprint does not address.",
    "Whether MJ-1's bivalent inhibition of BPTF translates into cellular or in vivo efficacy.",
    "Cell-based selectivity of the HDAC6 macrocycle across the HDAC family."
  ],
  "decision_card": {
    "useful_for": [
      "VCs diligencing undruggable-target pitches in oncology and epigenetics",
      "Teams weighing de novo binder, bivalent, or macrocycle modalities"
    ],
    "not_for": [
      "Treating preclinical binder or inhibitor results as clinical candidates"
    ],
    "compare_against": [
      "Existing small-molecule approaches to the same targets and their failure modes"
    ]
  },
  "writer": {
    "agent": "muse",
    "run_id": "2026-10-18T00"
  },
  "corrections": [],
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      "manifest_id": "1792232006426336673",
      "title": "MYC targeted de novo binders impair tumor growth",
      "source_name": "biorxiv-protein-structure-drug-discovery",
      "source_url": "https://biorxiv.org/content/10.64898/2026.10.15.758618v1.full",
      "published_date": "2026-10-16"
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    {
      "manifest_id": "1792232006426784323",
      "title": "Bivalent Inhibitor Development for a Dynamic Epigenetic Tandem Reader Protein Using a Combinatorial Histone Code",
      "source_name": "biorxiv-protein-structure-drug-discovery",
      "source_url": "https://biorxiv.org/content/10.64898/2026.10.09.758058v1.full",
      "published_date": "2026-10-16"
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      "manifest_id": "1792232006425016485",
      "title": "Binding of a Macrocyclic Nonapeptide Inhibitor to Histone Deacetylase 6",
      "source_name": "biorxiv-protein-structure-drug-discovery",
      "source_url": "https://biorxiv.org/content/10.64898/2026.10.10.758213v1.full",
      "published_date": "2026-10-16"
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      "url": "https://hangingcontext.com/stories/2026-10-17/drug-discovery-back-to-the-bench/",
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