Table 2.
Selected inhibitors targeting the aberrant activity of KMT2 complexes in cancer. Several major targets can be distinguished, including the core subunits (DPY30, RBBP5, ASH2L, and WDR5); LEDGF and Menin present in both wild-type (wt) MLL and MLL-fusion protein (FP) complexes; and “additional” proteins such as DOT1L, BRD4, CBP/p300, and fusion proteins (ENL) present in MLL-FP complexes. Other approaches to inhibit the actions of the mutated KMT2s, such as KMT2C and KMT2D, in cancer involve the use of repression complex blockers or contained glycolysis. More details are provided in the main text. TNBC: triple-negative breast cancer; IRAK: IL-1 receptor-associated kinase; YEATS domain: Yaf9, ENL, AF9, Taf14, Sas5 domain; PARP1/2: Poly(ADP-ribose) polymerase 1/2.
| Mode of Action | Name of Inhibitor | Cellular Outcome | Targeted Cancer Cells | References |
|---|---|---|---|---|
| Targeting core subunits of COMPASS: | MM-401 (microcyclic peptidomimetic) |
myeloid differentiation/phenocopying KMT2A deletion | MLL-r leukemia cells in culture | [245,247] |
| Antagonizing the interaction of WDR5 and KMT2A | OICR-9429 (small-molecule antagonist) |
Inhibition of proliferation and induction of differentiation | Patient-derived AML cells expressing p30 | [211] |
| Inhibition of cancer cell growth | Various tumor cells with a TP53 gain-of function (GOF) mutation | [154] | ||
| Targeting DPY30 | Cell penetrating peptides (CPPs) derived from ASH2L | Inhibition of cancer cell growth | MLL-r leukemia cells/other MYC-dependent hematologic cancers | [287] |
| Blocking interaction of Menin with KMT2A | MI-463, MI-503 (small-molecule antagonist) |
Inhibition of progression of MLL leukemia in vivo vs. normal hematopoiesis | MLL-r leukemia cells/mouse model of MLL leukemia | [249] |
| M-525 (small-molecule antagonist) |
Suppression of MLL-regulated gene expression, leukemia cell growth inhibition | Various cell lines derived from MLL-r leukemia (MV4, MOLM-13, MOLM-14) | [250] | |
| MI-2-2 (small-molecule inhibitor) |
Inhibition of cell proliferation, downregulation of differentiation | MLL leukemia cells (KMT2A-F4 translocation) | [270,271] | |
| Blocking interaction of KMT2A with LEDGF | CP65 (cyclic peptide) | Impairment of clonogenic growth of primary murine MLL-AF9-expressing leukemic blasts | MLL-AF9 leukemia cells | [256] |
| Targeting DOT1L in KMT2A-rearranged complexes | EPZ004777 (S-adenosylmethionine-competitive inhibitor) |
Downregulation of leukemic genes, inhibition of H3K79, inhibition of proliferation | Leukemia cells bearing MLL-r/extension of survival in a mouse MLL xenograft model or complete tumor regression | [237,288] |
| EPZ-5676 (pinometostat) | [259] | |||
| Dissociation of interacting proteins from MYC regulatory elements | I-BET (via BRD4) |
Downregulation of MYC-regulated gene expression, inhibition of proliferation | Hematological cancers (MLL-r leukemia) | [242,262,289] |
| A-485 (via the catalytic core of CBP/300) | Inhibition of proliferation | Lineage specific tumor cells (hematological and prostate) | [263] | |
| Inhibitors of YEATS domain of AF9 and ENL (XL-13m) | Downregulation of leukemic gene drivers | MLL-r leukemia cells | [267,268] | |
| Stabilization of wt KMT2A | IRAK1/4 | Inhibition of cancer cells proliferation in vitro/in vivo | MLL-r leukemia cells | [240,290] |
| Restoration of normal gene expression in KMT2C mutant cells | GSK 126 (via a subunit of the polycomb repressive complex 2) | Impairment of cell proliferation, resetting the epigenetic balance of polycomb and compass function | Cells/tumors bearing mutations (PHD domain) in KMT2C | [174] |
| PARP1/2-depdenent DNA repair | Olaparib (PARP1/2 inhibitor) | Synthetic lethality of cancer cells | Cancer cells with low KMT2C levels (bladder cancer) | [195] |
| Pharmacologically contained glycolysis | Glycolytic inhibitors (2-deoxy-D-glucose (2-DG) |
Impediment of tumorigenic growth | Lung cancer cells with KMT2D mutations | [187] |
| Suppression of ADIPOR cytoplasmic signaling | AdipoRon (ADIPOR agonist) | Induction of cancer cell death through necroptosis | MIA PaCa-2 tumor cells/cancer cells isolated from patients with pancreatic cancer/TNBC cells | [206,282,283] |