AP1903
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AP1903
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CAS No:
195514-63-7
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Formula:
C78H98N4O20
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Chemical Name:
AP1903
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Synonyms:
2-piperidinecarboxylic acid, 1-((2S)-1-oxo-2-(3,4,5-trimethoxyphenyl)butyl)-, 2,2"-(1,2-ethanediylbis(imino(2-oxo-2,1-ethanediyl)oxy-3,1-phenylene((1R)-3-(3,4-dimethoxyphenyl)propylidene))) ester, (2S,2"S)-;AP 1903 reagent;AP1903;Rimiducid;UNII-H564L1W5J2;AP-1903;AP 1903;H564L1W5J2;Rimiducid [INN]
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CAS No:
Description
Rimiducid (AP1903) is a dimerizer agent that acts by cross-linking the FKBP domains, initiating Fas signaling and hence apoptosis.
Rimiducid is a lipid-permeable tacrolimus analogue and a protein dimerizer. It was designed to overcome limitations of current cellular immunotherapies used for cancer and other blood disorders by enhancing the control of the immune cell activity and function. When administered via chemically-inducible dimerization (CID) technologies, rimiducid binds to switch proteins and dimerizes them, triggering downstream signaling cascade. The combination use of rimiducid with immunotherapies for enhanced therapeutic effectiveness is currently under investigation.|Rimiducid is a lipid-permeable tacrolimus analogue with homodimerizing activity. Dimerizer drug AP1903 homodimerizes an analogue of human protein FKBP12 (Fv) which contains a single acid substitution (Phe36Val) so that AP1903 binds to wild-type FKBP12 with 1000-fold lower affinity. This agent is used to homodimerize the Fv-containing drug-binding domains of genetically engineered receptors such as the iCD40 receptor of the autologous dendritic cell vaccine BP-GMAX-CD1, resulting in receptor activation.
Drug Information
Investigated for use/treatment in bone marrow transplant and graft versus host disease.|Treatment of graft versus host disease
Rimiducis is used to activate inducible caspase-9 produced by a modified gene included in some CAR T-cell therapies. This activation produces rapid induction of apoptosis in activated modified T-cells and resolution of the signs and symptoms of graft versus host disease within 24 hours.
Rimiducid binds to a drug binding domain derived from human FK506-binding protein which is present on a modified form of inducible caspase-9. This binding results in dimerization and subsequent activation of caspase-9. This system was designed to function as a "safety switch" in CAR T-cell therapy used in hematological cancers. Retroviral vectors used in production of these modified cells preferentially integrate this gene nearby promoters associated with T-cell activation. This results in higher expression of the modified inducible caspase-9 product in activated T-cells. In practice, this allows for specific targeting of these active T-cells by rimiducid which results in a decrease in circulating cell numbers of over 90% in the setting of graft versus host disease. This specificity spares non-alloreactive T-cells and allows for successful reconstitution of the transplanted immune system from these cells.[24753538] Additionally, these non-alloreactive cells retain their sensitivity to rimiducid.
2-piperidinecarboxylic acid, 1-((2S)-1-oxo-2-(3,4,5-trimethoxyphenyl)butyl)-, 2,2'-(1,2-ethanediylbis(imino(2-oxo-2,1-ethanediyl)oxy-3,1-phenylene((1R)-3-(3,4-dimethoxyphenyl)propylidene))) ester, (2S,2'S)-
AP1903 Use and Manufacturing
Human drugs -> Rare disease (orphan)|Human Drugs -> EU pediatric investigation plans
Computed Properties
Molecular Weight:1411.6
XLogP3:11.9
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:20
Rotatable Bond Count:39
Exact Mass:1410.67744153
Monoisotopic Mass:1410.67744153
Topological Polar Surface Area:262
Heavy Atom Count:102
Complexity:2330
Defined Atom Stereocenter Count:6
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes