AP 1903

AP1903, also known as 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.

Product information

CAS Number: 195514-63-7

Molecular Weight: 1411.63

Formula: C78H98N4O20

Synonym:

AP-1903

Rimiducid

Chemical Name: (S,2R,2'R)-(1R,1'R)-((((ethane-1,2-diylbis(azanediyl))bis(2-oxoethane-2,1-diyl))bis(oxy))bis(3,1-phenylene))bis(3-(3,4-dimethoxyphenyl)propane-1,1-diyl) bis(1-((S)-2-(3,4,5-trimethoxyphenyl)butanoyl)piperidine-2-carboxylate)

Smiles: COC1=CC=C(CC[C@@H](OC(=O)[C@@H]2CCCCN2C(=O)[C@@H](CC)C2=CC(OC)=C(OC)C(=C2)OC)C2=CC(=CC=C2)OCC(=O)NCCNC(=O)COC2=CC(=CC=C2)[C@@H](CCC2=CC(OC)=C(C=C2)OC)OC(=O)[C@@H]2CCCCN2C(=O)[C@@H](CC)C2C=C(OC)C(OC)=C(C=2)OC)C=C1OC

InChiKey: GQLCLPLEEOUJQC-ZTQDTCGGSA-N

InChi: InChI=1S/C78H98N4O20/c1-13-57(53-43-67(93-7)73(97-11)68(44-53)94-8)75(85)81-37-17-15-25-59(81)77(87)101-61(31-27-49-29-33-63(89-3)65(39-49)91-5)51-21-19-23-55(41-51)99-47-71(83)79-35-36-80-72(84)48-100-56-24-20-22-52(42-56)62(32-28-50-30-34-64(90-4)66(40-50)92-6)102-78(88)60-26-16-18-38-82(60)76(86)58(14-2)54-45-69(95-9)74(98-12)70(46-54)96-10/h19-24,29-30,33-34,39-46,57-62H,13-18,25-28,31-32,35-38,47-48H2,1-12H3,(H,79,83)(H,80,84)/t57-,58-,59-,60-,61+,62+/m0/s1

Technical Data

Appearance: Solid Power.

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: Soluble in DMSO, not in water

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥360 days if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined.

HS Tariff Code: 382200

How to use

In Vitro:

The human fibrosarcoma line HT1080 is engineered to express stably a fusion protein comprising a myristoylation sequence, two copies of F36V-FKBP, and the human first apoptosis signal (Fas) intracellular domain. Rimiducid (AP1903) elicits potent and dose-dependent apoptotic death of these engineered cells in culture, with an EC50 of ≈0.1 nM. Maximal killing occurred in the presence of 3 to 10 nM Rimiducid (AP1903), and the IC50 is approximately 0.2 nM. LV′VFas-transduced T lymphocytes expressing high levels of CD25 (top panel) are eliminated by with 66%±7.5% (n=10) efficiency. When cells are examined after CD25 expression returned to basal levels, 63%±4.7% (n=9) killing is observed after Rimiducid treatment.

In Vivo:

Rimiducid (AP1903; i.v., 0.01, 0.1, 1, 10, and 100 mg/kg) elicits a dose-dependent decrease in serum human GH levels, with a half-maximal effective dose of 0.4±0.1 mg/kg.

References:

1. Zhou X, Dotti G, Krance RA, Martinez CA, Naik S, Kamble RT, Durett AG, Dakhova O, Savoldo B, Di Stasi A, Spencer DM, Lin YF, Liu H, Grilley BJ, Gee AP, Rooney CM, Heslop HE, Brenner MK. Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation. Blood. 2015 May 14. pii: blood-2015-02-628354. [Epub ahead of print] PubMed PMID: 25977584.
2. Gargett T, Brown MP. The inducible caspase-9 suicide gene system as a "safety switch" to limit on-target, off-tumor toxicities of chimeric antigen receptor T cells. Front Pharmacol. 2014 Oct 28;5:235. doi: 10.3389/fphar.2014.00235. eCollection 2014. Review. PubMed PMID: 25389405; PubMed Central PMCID: PMC4211380.
3. Sadelain M. Eliminating cells gone astray. N Engl J Med. 2011 Nov 3;365(18):1735-7. doi: 10.1056/NEJMe1109971. PubMed PMID: 22047566.

Products are for research use only. Not for human use.