Phase-2 dossier: the menin MBM1 pocket - the only candidate here that is already de-risked, and therefore the only one whose gate is clinical

[
  {
    "pdb": "4GQ6",
    "title": "Human menin in complex with MLL peptide",
    "method": "X-ray",
    "resolution_A": 1.55
  },
  {
    "pdb": "7UJ4",
    "title": "Inhibition of Human Menin by SNDX-5613",
    "method": "X-ray",
    "resolution_A": 1.96
  },
  {
    "pdb": "3U88",
    "title": "Crystal structure of human menin in complex with MLL1 and LEDGF",
    "method": "X-ray",
    "resolution_A": 3
  }
]

[
  "no structure of menin with an intact KMT2A fusion protein",
  "no AlphaFold model of full-length KMT2A (AF-Q03164-F1 returns HTTP 404)"
]

{
  "id": "AF-O00255-F1",
  "global_plddt": 84.44,
  "fraction_plddt_very_low": 0.197
}

{
  "whole_blood": 8.197,
  "min": {
    "tissue": "Heart_Left_Ventricle",
    "tpm": 5.113
  },
  "max": {
    "tissue": "Brain_Cerebellum",
    "tpm": 45.145
  },
  "n_tissues": 54
}

{
  "pLI": 0.9999999992,
  "oe_lof": 0.1035,
  "loeuf": 0.2042
}

{
  "chembl_target": "CHEMBL1615381",
  "rows_pchembl_ge_6": 499,
  "best": {
    "molecule": "CHEMBL5267644",
    "type": "Ki",
    "value_nM": 0.104,
    "pchembl": 9.98
  }
}

{
  "G1_feasibility": {
    "question": "Can a KMT2A-versus-JUND displacement assay pair be built?",
    "GO": "Both fluorescence-polarisation assays running with Z-prime above 0.6 and a validated positive control",
    "STOP": "JUND peptide displacement assay cannot be made to give a dose response at all"
  },
  "G2_biology": {
    "question": "Frontline infant value",
    "GO": "Adding a menin inhibitor to Interfant-style induction raises the fraction of infants reaching consolidation MRD-negative by at least 15 absolute points",
    "STOP": "Improvement below 5 absolute points, or any increase in induction mortality",
    "ambiguous_zone": "5 to 15 points",
    "tie_breaker": "Event-free survival at 12 months in the same cohort, pre-specified"
  },
  "G3_window": {
    "question": "Is there an endocrine or haematopoietic cost of frontline exposure in infants?",
    "GO": "No grade 3 or higher differentiation syndrome above the published relapsed-setting rate, and normal CD34+ CFU recovery by day 28",
    "STOP": "Any treatment-related death attributable to differentiation syndrome in the first ten infants"
  }
}

{
  "_why": "Added by king sweep 2026-09-21 (Q82 corrections-owed #3). This entry quotes the menin-MBM1 53 nM figure. That number is NOT comparable to the KMT2A CXXC-DNA affinities without stating its buffer, and the omission is how a 1,300-fold 'discrepancy' was manufactured.",
  "value": "53 nM",
  "motif": "KMT2A MBM1, residues 4-15, FITC-labelled peptide at 15 nM",
  "method": "fluorescence polarisation",
  "buffer": "50 mM Tris, pH 7.5, 50 mM NaCl, 1 mM DTT",
  "nacl_mM": 50,
  "companion_itc": "72 nM by ITC, 50 mM phosphate pH 7.5, 50 mM NaCl, 1 mM beta-mercaptoethanol, 27 C",
  "source_pmid": "20961854",
  "source_quote": "\"in the FP buffer (50 mM Tris, pH 7.5, 50 mM NaCl, 1 mM DTT) used for binding experiments (Kd measurements)\" -- Grembecka 2010 JBC, Methods, fetched and read from PMC3003368 on 2026-09-21",
  "do_not_compare_naively": {
    "against": "KMT2A CXXC-DNA Kd 44 uM (PMID 20010842, Cierpicki 2010)",
    "because": "that measurement was made at 300 mM NaCl -- verbatim from its Methods, \"50 mM phosphate buffer (pH 7.1), 300 mM NaCl, 2 mM DTT at 25 C\" (PMC2908503, read 2026-09-21) -- SIX-FOLD more salt, on a salt-sensitive protein-DNA contact, against a hydrophobic peptide pocket that is not.",
    "best_matched_pair": "44 uM at 300 mM NaCl vs the 5.7 uM tagless CXXC measurement at 150 mM NaCl gives 108-fold against menin, not ~1,000-fold",
    "see": "ana-the-menin-affinity-comparison-was-made-at-one-sixth-the-salt"
  },
  "added": "2026-09-21"
}

{
  "_why": "Added by king sweep 2026-09-21 (cycle 46). This entry quotes the KMT2A CXXC-DNA 44 uM. That number is a property of five choices, not of the molecule, and quoting it bare is how this graph manufactured a 1,300-fold 'discrepancy' with the menin contact.",
  "value": "44 uM",
  "construct": "isolated CXXC domain, KMT2A 1147-1203, untagged, 15N-labelled",
  "ligand": "DNA pal oligonucleotide, one CpG element",
  "method": "NMR titration",
  "buffer": "50 mM phosphate, pH 7.1, 300 mM NaCl, 2 mM DTT, 25 C",
  "nacl_mM": 300,
  "source_pmid": "20010842",
  "source_quote": "\"Determination of the dissociation constants by NMR for the CXXC domain (MLL 1147-1203) and mutants was performed by titration of 15N-labeled protein with concentrated solutions of DNA pal oligonucleotide. Experiments were carried out in 50 mM phosphate buffer (pH 7.1), 300 mM NaCl, 2 mM DTT at 25 C.\" -- Cierpicki 2010 NSMB, Methods, fetched and read from PMC2908503 on 2026-09-21. The result sentence reads \"The wild type protein yielded a Kd of 44 uM\".",
  "this_is_the_high_salt_end": "300 mM NaCl is roughly twice physiological ionic strength and SIX TIMES the 50 mM the menin-MBM1 53 nM was measured in. The same domain measured tagless at 150 mM NaCl gives 5.7 uM -- 7.7-fold tighter from salt alone.",
  "do_not_compare_naively": {
    "against": "menin-MBM1 53 nM (PMID 20961854), measured at 50 mM NaCl by FP",
    "best_matched_pair": "108-fold, not ~1,000-fold",
    "see": "ana-the-menin-affinity-comparison-was-made-at-one-sixth-the-salt"
  },
  "added": "2026-09-21"
}