SGC-iMLLT - the MLLT1/MLLT3 YEATS chemical probe, and the 2026 paper that put it into KMT2A::AFF1 in vivo with a healthy-HSPC comparison
also called SGC-iMLLT · iMLLT · MLLT1/3 YEATS chemical probe
SGC-iMLLT is a freely available research compound that blocks a small reading head on two proteins, ENL and AF9, which help leukemia cells keep the wrong genes switched on. A 2026 study showed it slows the growth of the specific infant-leukemia fusion this project is built around, in animals, without damaging healthy blood stem cells.
The same thing, for a scientist
The first-in-class small-molecule chemical probe for the YEATS domain of MLLT1 (ENL/YEATS1) and MLLT3 (AF9/YEATS3), reported in 2018 with selectivity over YEATS2/4 and over bromodomains, cellular target engagement of both paralogues, and the first small-molecule X-ray co-crystal structures with the MLLT1 YEATS domain [E1]. This corpus already used it in ten entries as the discriminating reagent in the t(11;19) YEATS-retention argument [E3]. **What is new and was absent from every node file here: a 2026 Exp Hematol study from the Milne and Wilkinson groups reports that SGC-iMLLT downregulates MLLT1 target genes and strongly inhibits KMT2A::AFF1-driven leukaemia growth in vitro AND in vivo, while not altering in vitro colony-forming potential of human HSPCs or long-term in vivo function of mouse HSPCs** [E2]. That is a therapeutic-window measurement in the index fusion, and it is the strongest published counterweight to this corpus's standing objection that a YEATS antagonist in a non-YEATS fusion can only be acting on wild-type ENL. **It does not remove the objection - it makes it the interesting question**, because KMT2A::AFF1 carries no YEATS domain at all, so whatever SGC-iMLLT is doing in MV4;11 and its relatives is wild-type-ENL biology with a therapeutic window attached.
What the 2026 paper adds that this corpus did not have
Before it, the corpus's SGC-iMLLT evidence was: the 2018 probe paper 1; and a 2023 Leukemia paper in which HB1119 (YEATS-retaining MLL-ENL) and MV4;11 were both more sensitive at 2 uM than KOPN-8, with the MV4;11 sensitivity attributed by those authors to wild-type ENL, and with all four human lines sensitive at 20 uM where the authors themselves flag possible cytotoxicity 3.
That left the corpus with a single-concentration discriminating observation and no animal data. The 2026 paper adds:
- an explicit KMT2A::AFF1 framing rather than an 'MLL-r' one, in the title;
- in vivo efficacy, not just in vitro;
- target-gene downregulation (MLLT1 targets), so the effect is not a bare viability readout;
- a normal-tissue arm on both sides of the species divide - human HSPC colony-forming assays and mouse HSPC long-term in vivo function.
The normal-tissue arm is the part this project should weight most. gene-mllt1 already records the asymmetry that MLLT3/AF9 governs human HSC self-renewal and engraftment, which is the standing reason not to treat AF9 as a safe off-target for a dual MLLT1/3 probe. A probe that hits both paralogues and spares long-term mouse HSC function is a direct test of that worry, and it passed.
The interpretive problem this creates, stated plainly
KMT2A::AFF1 does not contain a YEATS domain. Every direct 5'-KMT2A fusion to AFF1 keeps the KMT2A N-terminus and the AFF1 C-terminus; there is no ENL and no AF9 in the oncoprotein. So a YEATS-domain antagonist cannot be acting on the fusion's own reader.
Three accounts remain, and the paper does not separate them:
- Wild-type ENL is required by the fusion's programme. ENL is a component of the AF4-family/P-TEFb elongation machinery that KMT2A::AFF1 engages, so blocking its reader function could throttle elongation at fusion targets without touching the fusion.
- Wild-type ENL is a general AML dependency and KMT2A::AFF1 lines are simply AML/ALL lines. This corpus already warns that the 'ENL-dependent leukaemia' framing comes from CRISPR and degradation work in lines that are mostly not t(11;19).
- The compound is doing something off-YEATS at the concentrations used. The 2023 paper's own note that 20 uM may be cytotoxic is the reason to keep this on the list.
The discriminating experiment is a YEATS aromatic-cage mutant rescue in a KMT2A::AFF1 line, which would separate 1 and 2 from 3 and is not reported anywhere.
| target | gene-mllt1 |
|---|---|
| secondary target | gene-mllt3 |
| modality | small molecule chemical probe (SGC open probe) |
| mechanism | competitive inhibitor of the MLLT1/MLLT3 YEATS acyl-lysine reader pocket; blocks YEATS-histone interaction |
| status | chemical probe only; no clinical candidate, no IND, no trial |
| selectivity | selective over YEATS2 and YEATS4 and over bromodomains, per the probe paper; does NOT distinguish MLLT1 from MLLT3 |
| evidence in index fusion | KMT2A::AFF1: growth inhibited in vitro and in vivo with MLLT1 target-gene downregulation (PMID 42242459); MV4;11 sensitive at 2 uM (PMID 36435883). KMT2A::AFF1 contains NO YEATS domain, so both results are wild-type-ENL biology. |
| absence class | never-measured |
| absence class basis | No YEATS aromatic-cage mutant rescue has been run in a KMT2A::AFF1 line, so the on-target basis of the 2026 in vivo efficacy is unestablished. |
structures
[ "6HT1" ]
key ae
[ "none reported; no in vivo toxicology beyond the 2026 mouse HSPC long-term function arm" ]
resistance
[ "SGC-iMLLT itself: not screened; no resistance selection has been reported for this probe.", "CORRECTED 2026-09-24 (Q187) - the previous blanket claim that no resistance selection has been reported for ANY YEATS antagonist is FALSE. A CRISPR-Cas9-mediated mutagenesis screen uncovered an ENL mutation conferring resistance to the ENL YEATS antagonist TDI-11055, and the authors used it as the on-target validation for that compound (PMID 36053276, doi:10.1158/2159-8290.CD-21-1307). Class-level resistance to YEATS-domain displacement is therefore both achievable and already demonstrated, and the resistance allele is published." ]
trials
[]
measurements
[
{
"quantity": "sensitivity_ranking",
"subject": "SGC-iMLLT at 2 uM | HB1119 and MV4;11 vs KOPN-8",
"value": 1,
"units": "ordinal (1 = HB1119/MV4;11 more sensitive than KOPN-8)",
"n": 4,
"universe": "four human t(11;19)-panel lines, single concentration, PMID 36435883 as read by this corpus",
"null": 0,
"note": "null is no difference between YEATS-retaining and YEATS-less MLL-ENL lines; at 20 uM all four are sensitive and the contrast disappears"
}
]- KMT2A::AFF1 has no YEATS domain, so efficacy here is a wild-type-ENL effect and there is no reason to expect it to be selective for KMT2A-rearranged disease. A trial designed on a fusion-stratified hypothesis would be designed on the wrong premise.
- MLLT3/AF9 depletion prevents maintenance of transplantable human HSPCs. A dual MLLT1/3 antagonist therefore carries a stem-cell liability by construction, and a colony-forming assay is the least sensitive way to look for it; the mouse long-term arm is the one that matters and it is a single study.
- The corpus's own t(9;11) breakpoint distribution says a YEATS-domain agent has no fusion target in 99.5% of t(9;11) patients. Positioning this class as a KMT2A-rearranged therapy selects an almost disjoint population from any YEATS-retention eligibility criterion.
- No resistance selection has ever been run against a YEATS antagonist, so the liability list here is empty for want of looking, not for want of liabilities.
- Which cell lines were in the 2026 'panel of leukemia cell lines', and at what concentration and schedule was the in vivo arm run? The abstract names none of it and the full text is not in PMC.
- Does a YEATS aromatic-cage mutant of wild-type ENL rescue SGC-iMLLT sensitivity in a KMT2A::AFF1 line? Without that, on-target action in the index fusion is assumed, not shown.
- The probe is dual MLLT1/MLLT3 and MLLT3 governs human HSC self-renewal. Is the clean human-HSPC colony result explained by short exposure, by a colony assay being insensitive to a self-renewal defect, or by a genuine window? The mouse long-term arm argues for the third but the three are not separated.
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
SGC-iMLLT is the first small-molecule chemical probe for the YEATS domain of MLLT1 and MLLT3, potent and selective for MLLT1/3-histone interactions with selectivity over YEATS2/4 and bromodomains, with demonstrated cellular target engagement and the first small-molecule X-ray co-crystal structures with the MLLT1 YEATS domain.
Discovery of an MLLT1/3 YEATS Domain Chemical Probe. · Moustakim M, Christott T, Monteiro OP, Bennett J, Giroud C, Ward J, Rogers CM, Smith P, Panagakou I, Diaz-Saez L, Felce SL, Gamble V, Gileadi C, Halidi N, Heidenreich D, Chaikuad A, Knapp S, Huber KVM, Farnie G, Heer J, Manevski N, Poda G, Al-Awar R, Dixon DJ, Brennan PE, Fedorov O · Angew Chem Int Ed Engl 2018What this evidence cannot show
Abstract read from the eutils record on 2026-09-24; the full text was not opened. No potency value, no cellular IC50 and no in vivo or pharmacokinetic data are stated in the abstract, so this citation supports the existence, selectivity class and structural validation of the probe and nothing quantitative.
Evidence that argues against this (1)
- A dual MLLT1/MLLT3 probe cannot separate the two paralogues, and MLLT3/AF9 governs human HSC self-renewal and engraftment, so on-target activity against AF9 is a plausible normal-tissue liability that a probe paper is not designed to detect. Oncofusion Knowledge Graph 2026
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
SGC-iMLLT downregulated MLLT1 target genes and strongly inhibited KMT2A::AFF1-driven leukaemia growth in vitro and in vivo, while not altering the in vitro colony-forming potential of human HSPCs or the long-term in vivo function of mouse HSPCs.
Inhibition of MLLT1 Limits Growth of KMT2A::AFF1 Leukemias Without Killing Healthy Hematopoietic Stem Cells. · Rajhansa S, Crump NT, Khoo HM, Dopico-Fernandez A, Bozhilov Y, Brennan PE, Fedorov O, Adams C, Farnie G, Milne TA, Wilkinson AC · Exp Hematol 2026What this evidence cannot show
Abstract read from the eutils record on 2026-09-24; the full text was not opened and is not in PMC as of that date. No concentration, no dose, no schedule, no cell-line identities and no effect sizes are stated in the abstract - 'a panel of leukemia cell lines' is as specific as it gets - so nothing quantitative should be carried forward from this citation. The absence of an effect on HSPCs is a negative result in a normal-tissue assay whose power is not stated.
Evidence that argues against this (1)
- KMT2A::AFF1 carries no YEATS domain, so SGC-iMLLT cannot be acting on a reader inside this fusion. A 2023 Leukemia study reached the same observation - MV4;11 as sensitive as the YEATS-retaining HB1119 at 2 uM - and attributed it to a role for WILD-TYPE ENL, which means an efficacy result in KMT2A::AFF1 is not evidence about fusion-borne YEATS and may not be selective for KMT2A-rearranged disease at all. Leukemia 2023
- E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
In a t(11;19) line panel, greater sensitivity to SGC-iMLLT at 2 uM was seen for HB1119 (YEATS-retaining MLL-ENL) and MV4;11 than for KOPN-8 (YEATS-less MLL-ENL), and all four human lines were sensitive at 20 uM where the authors note possible cytotoxicity.
The ENL YEATS epigenetic reader domain critically links MLL-ENL to leukemic stem cell frequency in t(11;19) Leukemia. · Hu H, Saha N, Yang Y, Ahmad E, et al. · Leukemia 2023What this evidence cannot show
Quoted from this corpus's own reading of the paper in line-hb11-19-is-yeats-positive-and-reciprocal-positive and line-kopn-8-kmt2a-mllt1-infant-yeats-negative, which record that the full text was reached via the PMC HTML page after two other routes failed. I did not re-open the paper this cycle; the discriminating observation rests on a single concentration in that entry's own assessment.
Evidence that argues against this (1)
- MV4;11 has no ENL YEATS domain at all and was as sensitive as HB1119 at 2 uM, so SGC-iMLLT sensitivity is not a clean readout of fusion-borne YEATS - which is the corpus's own recorded objection and the reason the 2026 in vivo result needs a mechanism arm. Leukemia 2023
- E4established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
A CRISPR-Cas9-mediated mutagenesis screen uncovered an ENL mutation that confers resistance to TDI-11055, an orally bioavailable small-molecule ENL inhibitor that displaces ENL from chromatin by blocking its YEATS domain interaction with acylated histones; the authors present the resistance allele as validation of on-target activity.
Small-Molecule Inhibition of the Acyl-Lysine Reader ENL as a Strategy against Acute Myeloid Leukemia. · Liu Y, Li Q, Alikarami F, Barrett DR, et al. · Cancer Discov 2022What this evidence cannot show
TDI-11055 is a different chemical series from SGC-iMLLT and targets the ENL/MLLT1 YEATS domain; this establishes that the YEATS-displacement mechanism is escapable by point mutation, not that SGC-iMLLT resistance has been selected. The specific residue was not extracted this cycle - only the abstract was read - so the allele should be pulled from the full text before it is used to design a resistance assay.
Evidence that argues against this (1)
- A resistance allele selected against ENL YEATS in AML may not transfer to the index fusion at all. KMT2A::AFF1 contains NO YEATS domain, and this entry already records that MV4;11 - a KMT2A::AFF1 line - was as sensitive to SGC-iMLLT at 2 uM as the YEATS-retaining MLL-ENL line HB1119, so YEATS-antagonist sensitivity in the index fusion is wild-type ENL biology rather than fusion-borne. An ENL point mutation that rescues an AML line from TDI-11055 therefore does not establish that the same escape is available, or sufficient, where the drug acts on wild-type ENL in trans. Leukemia 2023
competitive antagonist of the MLLT1 YEATS acyl-lysine reader pocket; co-crystal 6HT1
same probe, same pocket on AF9; the probe does not distinguish the two paralogues
- treated by →KMT2A::AFF1 (MLL-AF4), t(4;11)(q21;q23)
2026 Exp Hematol: inhibits KMT2A::AFF1 leukaemia growth in vitro and in vivo while sparing human and mouse HSPC function - and KMT2A::AFF1 carries no YEATS domain
supplies the in vivo and normal-tissue arms the dossier lacked, in the index fusion
the agent-name instrument surfaced this probe's 2026 in vivo paper, which was in no node file
the probe whose pocket occupancy is scaffold-blind by construction
the probe and the 2026 in vivo window this scoring turns on
one of four named YEATS antagonists in the bounding name list; its data.resistance field is contradicted by PMID 36053276
published window is two haematopoietic endpoints, neither of which can see this