Hypothesis: menin inhibitors differ in how much JUND they liberate, and the least JUND-liberating compound will be the most durable

[
  "In a head-to-head fluorescence-polarisation counter-screen with MBM1 and JUND peptides, the menin-inhibitor class shows a spread of at least 5-fold in KMT2A-versus-JUND displacement ratio.",
  "Compounds with lower JUND displacement produce less JUND chromatin gain by CUT&RUN and less upregulation of JUND target genes at matched menin displacement.",
  "Adding a JNK inhibitor benefits the high-JUND-displacement compounds more than the low-displacement ones, which is a clean interaction test.",
  "If the endocrine mandate is also pocket-mediated, the same ranking predicts the parathyroid-hormone signal across compounds, which can be checked against existing label and trial data rather than generated.",
  "Boltz or comparable co-folding of menin with each peptide and each ligand recovers the experimentally measured selectivity ranking, validating the computational route for designing a selective ligand."
]

[]

[
  "ana-menin-partner-selectivity-profiling"
]

[
  "All menin inhibitors displace JUND to within 2-fold of each other, which would make JUND liberation a target property rather than a compound property and remove any design opportunity.",
  "JUND displacement across compounds shows no relationship to JUND chromatin gain or to durability in models.",
  "Structural and computational analysis finds no exploitable difference between the MLL1 and JUND binding modes, killing the strong form outright.",
  "The JUND resistance mechanism fails to replicate in an independent group, in which case there is nothing to select against."
]

{
  "_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"
}