H3B-8800

Overview

H3B-8800 is an orally bioavailable small-molecule splicing modulator that targets the SF3b complex (specifically SF3B1) to inhibit aberrant pre-mRNA splicing. It was developed for cancers harboring spliceosome mutations (e.g., SF3B1, SRSF2, U2AF1). A prior phase I trial (NCT02841540) demonstrated limited monotherapy efficacy with dose-limiting toxicity, motivating investigation of lower-dose combination regimens.

Evidence in the corpus

  • H3B-8800 showed preferential in vitro activity against SF3B1-mutant/del(13q) double-mutant (DM) CLL cells (IC50 0.00346 μM) versus Mdr-only CLL cells (IC50 0.05331 μM); combined with temsirolimus, the Chou-Talalay combination index was 3.56 × 10^-6 in DM cells (more synergistic than in Mdr-only cells, CI 1.96 × 10^-4) PMID:26200345.
  • In vivo (NSG engraftment model), H3B-8800 (4 mg/kg oral, 5 days) + temsirolimus extended median OS of DM CLL mice from 9 to 27 days (3-fold, P<0.01 log-rank) versus negligible benefit in Mdr-only CLL mice PMID:26200345.
  • Human CLL patient samples carrying both SF3B1 mutation and del(13q) (n=3) were significantly more sensitive to the H3B-8800 + temsirolimus combination than SF3B1-mut alone, del(13q) alone, or double-negative groups (P<0.001, 2-way ANOVA) PMID:26200345.
  • Authors note that H3B-8800 monotherapy was limited by toxicity in the prior phase I trial; lower-dose combination with temsirolimus may be more tractable clinically PMID:26200345.

Resistance mechanisms

  • Mdr-only (del(13q), SF3B1-WT) CLL cells showed markedly lower sensitivity to H3B-8800 (IC50 0.05331 μM vs 0.00346 μM in DM cells), suggesting SF3B1 mutation is required for strong single-agent response PMID:26200345.

Cancer types (linked)

Sources

  • PMID:26200345 — SF3B1-mutant/del(13q) CLL mouse model; H3B-8800 + temsirolimus combination synergistic in vitro and in vivo in DM CLL cells; human CLL patient samples confirm selectivity for double-mutant genotype.

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