Identification

Generic Name
H3B-8800
DrugBank Accession Number
DB14017
Background

H3B-8800 is a novel spliceosome inhibitor developed by H3 Biomedicine 4. 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 1. 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 4.

Type
Small Molecule
Groups
Investigational
Structure
Thumb
Weight
Average: 555.716
Monoisotopic: 555.330836181
Chemical Formula
C31H45N3O6
Synonyms
Not Available
External IDs
  • H3B 8800
  • H3B-8800
  • H3B8800

Pharmacology

Indication

Not Available

Pharmacology
Reduce drug development failure rates
Build, train, & validate machine-learning models
with evidence-based and structured datasets.
See how
Build, train, & validate predictive machine-learning models with structured datasets.
See how
Contraindications & Blackbox Warnings
Contraindications
Avoid life-threatening adverse drug events
Improve clinical decision support with information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.
Learn more
Avoid life-threatening adverse drug events & improve clinical decision support.
Learn more
Pharmacodynamics

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 1,2. 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 1,3.

Mechanism of action

H3B-8800 is thought to bind to a site similar to pladienolides on the SF3B complex within the spliceosome 1. 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 1. 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 2. 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 1,3.

TargetActionsOrganism
ASplicing factor 3B subunit 1
inhibitor
Humans
Absorption

Not Available

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism
Not Available
Route of elimination

Not Available

Half-life

Not Available

Clearance

Not Available

Adverse Effects
Adverseeffects
Improve decision support & research outcomes
With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates.
Learn more
Improve decision support & research outcomes with our structured adverse effects data.
Learn more
Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions
Not Available

Categories

Drug Categories
Not Available
Classification
Not classified
Affected organisms
Not Available

Chemical Identifiers

UNII
90YLS47BRX
CAS number
1825302-42-8
InChI Key
YOIQWBAHJZGRFW-WVRLKXNASA-N
InChI
InChI=1S/C31H45N3O6/c1-22(26-11-6-7-16-32-26)9-8-10-23(2)29-24(3)12-13-27(39-30(37)34-19-17-33(5)18-20-34)31(4,38)15-14-25(35)21-28(36)40-29/h6-13,16,22,24-25,27,29,35,38H,14-15,17-21H2,1-5H3/b9-8+,13-12+,23-10+/t22-,24+,25-,27+,29-,31-/m1/s1
IUPAC Name
(2S,3S,4E,6S,7R,10R)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(4E,6R)-6-(pyridin-2-yl)hepta-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl 4-methylpiperazine-1-carboxylate
SMILES
C[C@H](\C=C\C=C(/C)[C@H]1OC(=O)C[C@H](O)CC[C@@](C)(O)[C@@H](OC(=O)N2CCN(C)CC2)\C=C\[C@@H]1C)C1=CC=CC=N1

References

General References
  1. Seiler M, Yoshimi A, Darman R, Chan B, Keaney G, Thomas M, Agrawal AA, Caleb B, Csibi A, Sean E, Fekkes P, Karr C, Klimek V, Lai G, Lee L, Kumar P, Lee SC, Liu X, Mackenzie C, Meeske C, Mizui Y, Padron E, Park E, Pazolli E, Peng S, Prajapati S, Taylor J, Teng T, Wang J, Warmuth M, Yao H, Yu L, Zhu P, Abdel-Wahab O, Smith PG, Buonamici S: H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers. Nat Med. 2018 May;24(4):497-504. doi: 10.1038/nm.4493. Epub 2018 Feb 19. [Article]
  2. Fei DL, Motowski H, Chatrikhi R, Prasad S, Yu J, Gao S, Kielkopf CL, Bradley RK, Varmus H: Wild-Type U2AF1 Antagonizes the Splicing Program Characteristic of U2AF1-Mutant Tumors and Is Required for Cell Survival. PLoS Genet. 2016 Oct 24;12(10):e1006384. doi: 10.1371/journal.pgen.1006384. eCollection 2016 Oct. [Article]
  3. Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R, Sato Y, Sato-Otsubo A, Kon A, Nagasaki M, Chalkidis G, Suzuki Y, Shiosaka M, Kawahata R, Yamaguchi T, Otsu M, Obara N, Sakata-Yanagimoto M, Ishiyama K, Mori H, Nolte F, Hofmann WK, Miyawaki S, Sugano S, Haferlach C, Koeffler HP, Shih LY, Haferlach T, Chiba S, Nakauchi H, Miyano S, Ogawa S: Frequent pathway mutations of splicing machinery in myelodysplasia. Nature. 2011 Sep 11;478(7367):64-9. doi: 10.1038/nature10496. [Article]
  4. H3 Biomedicine Granted Orphan Drug Designation of H3B-8800 for Treatment of Acute Myelogenous Leukemia and Chronic Myelomonocytic Leukemia [Link]
ChemSpider
71360838

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1RecruitingTreatmentAcute Myeloid Leukemia (AML) / Chronic Myelomonocytic Leukemia (CMML) / Myelodysplastic Syndromes (MDS)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.153 mg/mLALOGPS
logP3.32ALOGPS
logP3.14ChemAxon
logS-3.6ALOGPS
pKa (Strongest Acidic)13.92ChemAxon
pKa (Strongest Basic)6.89ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area112.43 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity156.6 m3·mol-1ChemAxon
Polarizability62.34 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Drugtargets2
Build, predict & validate machine-learning models
Use our structured and evidence-based datasets to unlock new
insights and accelerate drug research.
Learn more
Use our structured and evidence-based datasets to unlock new insights and accelerate drug research.
Learn more
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Involved in pre-mRNA splicing as a component of the splicing factor SF3B complex (PubMed:27720643). SF3B complex is required for 'A' complex assembly formed by the stable binding of U2 snRNP to the branchpoint sequence (BPS) in pre-mRNA. Sequence independent binding of SF3A/SF3B complex upstream of the branch site is essential, it may anchor U2 snRNP to the pre-mRNA (PubMed:12234937). May also be involved in the assembly of the 'E' complex (PubMed:10882114). Belongs also to the minor U12-dependent spliceosome, which is involved in the splicing of rare class of nuclear pre-mRNA intron (PubMed:15146077).
Specific Function
Mrna binding
Gene Name
SF3B1
Uniprot ID
O75533
Uniprot Name
Splicing factor 3B subunit 1
Molecular Weight
145829.085 Da
References
  1. Yokoi A, Kotake Y, Takahashi K, Kadowaki T, Matsumoto Y, Minoshima Y, Sugi NH, Sagane K, Hamaguchi M, Iwata M, Mizui Y: Biological validation that SF3b is a target of the antitumor macrolide pladienolide. FEBS J. 2011 Dec;278(24):4870-80. doi: 10.1111/j.1742-4658.2011.08387.x. Epub 2011 Oct 31. [Article]
  2. Seiler M, Yoshimi A, Darman R, Chan B, Keaney G, Thomas M, Agrawal AA, Caleb B, Csibi A, Sean E, Fekkes P, Karr C, Klimek V, Lai G, Lee L, Kumar P, Lee SC, Liu X, Mackenzie C, Meeske C, Mizui Y, Padron E, Park E, Pazolli E, Peng S, Prajapati S, Taylor J, Teng T, Wang J, Warmuth M, Yao H, Yu L, Zhu P, Abdel-Wahab O, Smith PG, Buonamici S: H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers. Nat Med. 2018 May;24(4):497-504. doi: 10.1038/nm.4493. Epub 2018 Feb 19. [Article]

Drug created at April 26, 2018 19:12 / Updated at June 12, 2020 16:53