Jolanta Grembecka & Tomasz Cierpicki (University of Michigan) — the chemistry that made the menin interface druggable
also called Grembecka Lab · Cierpicki Lab · University of Michigan Pathology · MI-2 · MI-2-2 · menin-MLL inhibitors
Two chemists in Michigan made the first small molecules that block the grip between menin and MLL, and solved the crystal structure showing how. Everything in the clinic today descends from that chemistry.
The same thing, for a scientist
Jolanta Grembecka and Tomasz Cierpicki, in the Department of Pathology at the University of Michigan, reported the first small-molecule inhibitors of the menin-MLL fusion protein interaction binding menin with nanomolar affinity and reversing MLL-fusion-mediated transformation, then produced the first high-resolution crystal structure of human menin bound to such an inhibitor (MI-2), showing the compound occupies the MLL pocket and mimics MLL's key contacts, and used it to design MI-2-2 with Kd = 22 nM. They also characterised the bivalent nature of the menin-MLL interaction, which involves two N-terminal MLL fragments rather than one.
What they own that the Iqbal Lab does not1 deeper
A working, publication-proven pipeline for turning a protein-protein interface into a nanomolar small molecule. This is precisely the capability the lab's central hypothesis assumes exists and does not itself possess. The 2012 Nature Chemical Biology paper delivered the first menin-MLL inhibitors with nanomolar affinity and demonstrated functional reversal of transformation 1; the Blood paper delivered the co-crystal structure and used it to drive affinity to 22 nM 2.
Structural biology on menin specifically, including the insight that the interaction is bivalent - two N-terminal MLL fragments contact menin, not one 2. That detail matters strategically: a bivalent interface has two independently targetable sub-pockets, and a drug that occupies only one leaves the other. It is also relevant to why resistance mutations can kill drug binding while sparing MLL1 binding.
Fragment-based and NMR-driven methods applicable to the lab's other candidate interfaces. If the lab's thesis is that other obligate partners expose druggable surfaces, this is the group that can say, from experience, which surfaces are tractable and which are not.
Partnering angle: the most natural fit for the lab's actual hypothesis
Of every group in this survey, Michigan is the one whose capability most exactly complements the Iqbal Lab's stated programme. The lab proposes to identify obligate partner interfaces; Michigan can tell you whether an identified interface is chemically tractable and, if so, make the tool compound.
The proposition to put to them is: here is a ranked list of non-menin KMT2A::AFF1 obligate interfaces with predicted hot-spot residues, pocket descriptors, essentiality and toxicity dossiers. Which of these are worth a fragment screen? That is a question they are uniquely qualified to answer and that costs them little to consider.
Caution on competition. They are not a neutral service. They have their own compound series, likely patent positions and industry relationships around menin chemistry, and any interface they consider promising is one they could pursue themselves. The engagement should be framed and documented accordingly, and the lab's contribution (the target selection and its biological justification) needs to be independently publishable.
| group | Jolanta Grembecka and Tomasz Cierpicki (joint chemistry / structural biology programme) |
|---|---|
| institution | Department of Pathology, University of Michigan, Ann Arbor MI, USA (affiliation as printed on the 2012 papers; current status not separately verified) |
| focus | Small-molecule inhibition of protein-protein interactions in leukaemia; menin-MLL interface chemistry; fragment-based and structure-guided design; NMR and X-ray structural biology of chromatin-complex interfaces |
| partnering angle | The closest capability match to the lab's own hypothesis. Bring a ranked list of non-menin KMT2A::AFF1 obligate interfaces with predicted hot-spot residues, pocket descriptors, essentiality and toxicity dossiers, and ask which merit a fragment screen. They supply chemical tractability judgement and, potentially, tool compounds; the lab supplies target selection and biological justification. Document the arrangement: they are not a neutral service and hold their own IP positions. |
| relationship | complementary capability; potential competitor on any interface they decide to pursue themselves |
key papers
[
{
"title": "Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia",
"year": 2012,
"venue": "Nature Chemical Biology",
"pmid": "22286128",
"doi": "10.1038/nchembio.773"
},
{
"title": "Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemia",
"year": 2012,
"venue": "Blood",
"pmid": "22936661",
"doi": "10.1182/blood-2012-05-429274"
}
]leverage they hold
[ "structure-guided PPI inhibitor design pipeline with a proven success", "menin co-crystal structures and the bivalency insight", "fragment screening and protein NMR infrastructure", "likely patent estate around early menin-MLL chemical matter" ]
- A bivalent interface targeted at one sub-pocket is a structurally predictable resistance liability, and the clinical MEN1 escape mutations are consistent with exactly that.
- Engaging a chemistry group with its own IP position on the target class risks handing over the lab's best target-selection insight without a share of the resulting asset.
- Nanomolar affinity to a purified protein is a weak predictor of cellular or clinical efficacy; the DOT1L programme had excellent chemistry and failed anyway.
- The menin-MLL interaction is bivalent. Do the clinical inhibitors occupy both sub-pockets or only one, and does the unoccupied contact explain why MEN1 resistance mutations can abolish drug binding while preserving MLL1 binding?
- Which non-menin KMT2A::AFF1 interfaces are chemically tractable by the criteria this group actually uses? Their published selection logic has never been applied systematically across the fusion's full interactome.
- Michigan's current institutional and funding status, and whether either PI remains at Ann Arbor in 2026, were not verified here.
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
Grembecka and Cierpicki reported the first small-molecule inhibitors of the menin-MLL fusion protein interaction, binding menin with nanomolar affinity, reversing MLL-fusion-mediated leukemic transformation by downregulating target genes, and selectively blocking proliferation and inducing apoptosis and differentiation in MLL-translocated leukaemia cells.
Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia · Grembecka J, He S, Shi A, et al., Cierpicki T · Nature Chemical Biology 2012What this evidence cannot show
First-generation tool compounds with pharmacokinetic limitations; the clinical agents (revumenib, ziftomenib, bleximenib, enzomenib) are chemically distinct series from other groups and companies, so Michigan's priority claim is conceptual and structural rather than on the marketed molecules. Cell-line and transformation-assay endpoints only.
Evidence that argues against this (1)
- The first-in-class claim is historically accurate and its compounds were thienopyrimidine tool molecules with micromolar-to-submicromolar potency, not the clinical chemotypes. The line from that work to an approved drug ran through several distinct scaffolds, so citing it as the origin of menin inhibition overstates chemical continuity. Nature Chemical Biology 2012
- E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
The group solved the first high-resolution crystal structure of human menin bound to a small-molecule inhibitor (MI-2), showing the compound occupies the MLL pocket and mimics MLL's key contacts, characterised the menin-MLL interaction as bivalent involving two N-terminal MLL fragments, and used the structure to design MI-2-2 with Kd = 22 nM.
Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemia · Shi A, Murai MJ, He S, et al., Grembecka J, Cierpicki T · Blood 2012What this evidence cannot show
A crystal structure is a single low-energy conformation and does not capture the dynamics that determine whether a partial occupancy is functionally sufficient in a cell. The bivalency finding is structural; how much each of the two contacts contributes to the leukaemic requirement is a separate question the structure does not answer.
Evidence that argues against this (1)
- Qualifies the structural claim in a way that matters for the lab's thesis. This entry credits the group with the first menin-inhibitor co-crystal and with establishing bivalency, and its first open question asks whether clinical inhibitors occupy both sub-pockets and whether the unoccupied contact explains MEN1 resistance. The same group's 2026 Blood paper supplies part of the answer and it is not encouraging. Co-crystal structures of ziftomenib with menin wild-type, T349M and G331R show a similar binding mode across all three, yet ziftomenib loses potency against T349M and G331R relative to wild type and is outright resistant to M327I and G331D. A drug can therefore keep its binding pose and still lose the cell, which means the resistance problem at this interface is not solved by finding a pose that tolerates a mutation. Combined with the fact that M327I defeats both revumenib and ziftomenib, the picture is of a small set of interface residues that break chemically unrelated compounds -- the failure mode one expects when a single pocket, rather than a redundant surface, is the druggable handle. Caveats: engineered cell lines throughout, no patient material, and the paper's sponsor employees are co-authors. Read: abstract only; the structures themselves were not inspected. Miao H et al. 2026
- E3weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paper
The group remains active in the menin field and its members appear on current clinical menin-inhibitor literature.
Ziftomenib in relapsed or refractory acute myeloid leukaemia (KOMET-001): a multicentre, open-label, multi-cohort, phase 1 trial · Wang ES, ... Fathi AT · Lancet Oncology 2024What this evidence cannot show
This trial paper was returned by an author search for Grembecka but the specific authorship role, and whether the Michigan chemistry is connected to ziftomenib, were NOT verified in this pass. Do not assert any Michigan-Kura link on this basis. The citation is retained only as evidence that the field's clinical literature is active and current; the claim it supports is weak by design.
Evidence that argues against this (1)
- Replaces this entry's weakest evidence item and closes its third open question, and the answer is a larger conflict of interest than the entry records. E3 rests on a general 'remains active in the field' claim. The hard fact is better and sharper: in August 2026 Blood published 'Discovery and preclinical activity of the menin-KMT2A inhibitor ziftomenib in acute leukemia models', with Tomasz Cierpicki and Jolanta Grembecka as the last two authors, both affiliated to the Department of Pathology, University of Michigan, Ann Arbor. So (i) both PIs are still at Ann Arbor in 2026, which the entry lists as unverified; and (ii) the co-author list includes employees of Kura Oncology, Inc. (San Diego) and Wellspring Biosciences, Inc. (San Diego). This is the discovery-and-preclinical paper for ziftomenib, an FDA-approved commercial menin inhibitor, published jointly by this laboratory and its commercial sponsor. The entry's partnering_angle says 'they are not a neutral service and hold their own IP positions' and advises documenting the arrangement. That understates it. They are not a chemistry group adjacent to the menin field; they are inside one of the two approved menin-inhibitor programmes, in an active and currently publishing relationship with its sponsor. Any proposal that brings them a ranked list of non-menin KMT2A::AFF1 interfaces is handing target-selection work to a group with a live commercial partner in the same target class, and the entry should say so before a lab acts on its recommendation. Nothing here impugns anyone: the affiliations and co-authorships are printed on the paper. Read: abstract, author list and affiliations; not full text. Miao H et al. 2026
did the chemistry and the structures that made this pocket druggable
Counter-evidence (Miao 2026, PMID 41849234): the Michigan group are senior authors on ziftomenib's discovery/preclinical paper with Kura Oncology and Wellspring Biosciences co-authors -- they sit inside an approved commercial menin programme, not adjacent to it
Counter-evidence: ziftomenib keeps the same binding pose against T349M and G331R yet loses potency, and is resistant to M327I/G331D -- pose preservation does not rescue the interface
- ← related toKura Oncology — ziftomenib (KO-539): an adults-only sponsor that quietly supplies infant trials
Counter-evidence to the partnering plan: Kura's academic mechanism/chemistry slot is already occupied by the Michigan group, publishing jointly as of Blood 2026 (PMID 41849234)
first small-molecule inhibitors and first co-crystal structure of the menin-MLL interface; characterised it as bivalent
MI-2 and MI-2-2 (Kd 22 nM) bind the MLL pocket of menin and reverse MLL-fusion transformation
complementary chemistry capability, but a competitor on any interface they choose to pursue themselves