H3B-8800

H3B-8800 Uses, Dosage, Side Effects, Food Interaction and all others data.

H3B-8800 is a novel spliceosome inhibitor developed by H3 Biomedicine . It offers the benefit of preferentially killing spliceosome-mutant cancer cells whereas other splicesome inhibitors, such as the pladienolide analogue E7107, show no such preferential targeting . H3B-8800 was granted orphan drug status by the FDA in August 2017 and is in clinical trials for the treatment of acute myelogenous leukemia and chronic myelomonocytic leukemia .

H3B-8800 preferentially targets cells with spliceosome complexes containing mutant splicing factor 3B1 (SF3B1) protein, modulating intron splicing leading to increased death in cancer cells while having little effect on the viability cells with wild-type SF3B1 . Both normal and aberrant mature mRNA are suppressed in mutant and wild-type cells, the selectivity of the lethal effect is thought to be due to the presence of mutant SF3B1 and its implications rather than a change in mechanism or potency of effect on the mutant protein over the wild-type .

Trade Name	H3B-8800
Generic	H3B-8800
Type
Formula	C31H45N3O6
Weight	Average: 555.716 Monoisotopic: 555.330836181
Groups	Investigational
Therapeutic Class
Manufacturer
Available Country
Last Updated:	September 19, 2023 at 7:00 am

How H3B-8800 works

H3B-8800 is thought to bind to a site similar to pladienolides on the SF3B complex within the spliceosome . Once bound it induces increased retention of short (<300 nucleotide) GC-rich introns through modulation of pre-mRNA processing. These intron-retained mRNA sequences are then thought to be destroyed through the nonsense-mediated decay pathway. It has been suggested that modulation by H3B-8800 is mediated by disruption of branchpoint sequence recognition by the SF3B complex as there is overall less preference for adenosine as the branchpoint nucleotide and a greater amount of sequences with weaker association to the SFB3 in introns retained with H3B-8800.

It was found that 41 of 404 genes encoding spliceosome proteins contained GC-rich sequences whose retention was induced by H3B-8800 . It is suggested that this is key to the specificity of H3B-8800's lethality as cells with spliceosome-mutant cells are dependent on the expression of wild-type spliceosome components for survival . Since cancer cells, as in myelodysplasia, experience SF3B1 mutations much more frequently than host cells, this allows H3B-8800 to be used to preferentially target these cells by inducing intron-retention in critical spliceosome component pre-mRNA leading to destruction of the now nonsense mature RNA ultimately cell-death due to the lack of these critical proteins .

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