An oral allosteric inhibitor that breaks the mutant DNMT3A R882H/R878H homodimer could reverse established CHIP-like ...

IF a mutant-selective allosteric inhibitor of the DNMT3A R882H/R878H homodimer interface at PDB: 6W8B (target affinity Ki ≤500 nM by SPR) is administered by oral gavage at 15 mg/kg/day for 12 weeks to 12-month-old Vav1-Cre; Dnmt3a-R878H/+ mice of both sexes, compared with age-matched vehicle-treated knock-in littermates and 6-month reference controls,

THEN bone-marrow Lin-Sca1+cKit+ (LSK) cells will decrease by at least 40% by flow cytometry, plasma IL-6 and TNF-α will decrease by at least 30% by Luminex, the peripheral CD11b+Gr1+ / CD3+B220+ ratio will shift toward 6-month control levels, competitive transplant engraftment from treated donors will fall, and targeted bisulfite-seq will show methylation recovery at p15INK4b and RASSF1A; an exploratory downstream effect should be reduction of mutant monocyte-derived microglial signatures in aged tissues.

BECAUSE:

1. The provided Research Context identifies DNMT3A R882H/R878H as creating a targetable neomorphic homodimer interface at PDB: 6W8B, with TR-FRET nominated as the direct target-engagement assay [provided Research Context; no DOI/URL in retrieved literature].
2. [SPECULATIVE] Disrupting this mutant interface will restore a more normal methylation program at CHIP-relevant tumor-suppressor loci such as p15INK4b and RASSF1A, which can be distinguished from nonspecific cytotoxicity by paired bisulfite-seq and viability assays [provided Research Context; no DOI/URL in retrieved literature].
3. [SPECULATIVE] Recovery of methylation at these loci will reduce the competitive fitness of already-expanded mutant HSC clones, leading to contraction of the LSK compartment and improved competitive transplant performance [provided Research Context; no DOI/URL in retrieved literature].
4. Hematopoietic DNMT3A R882H can alter monocyte-derived microglial transcription/function and cause motor pathology in aging mice, implying that repairing the mutant hematopoietic state may also repair downstream myeloid tissue damage beyond marrow (DNMT3A R882H-mutant hematopoiesis alters MoMg and causes motor pathology)[https://doi.org/10.1101/2023.11.16.567402].

One-liner: An oral allosteric inhibitor that breaks the mutant DNMT3A R882H/R878H homodimer could reverse established CHIP-like clonal dominance, inflammaging, and downstream myeloid tissue injury in aged knock-in mice.

SENS category: OncoSENS

Key references: • doi.org/10.1101/2023.11.16.567402]. • PMID: 30122151 • PMID: 29988049