Rimiducid

Identification

Summary

Rimiducid is a homodimerizing agent potentially used in combination with cellular immunotherapies for cancers and blood disorders to increase the therapeutic effectiveness.

Generic Name
Rimiducid
DrugBank Accession Number
DB04974
Background

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.1,6 The combination use of rimiducid with immunotherapies for enhanced therapeutic effectiveness is currently under investigation.

Type
Small Molecule
Groups
Investigational
Structure
Thumb
Weight
Average: 1411.65
Monoisotopic: 1410.677441572
Chemical Formula
C78H98N4O20
Synonyms
  • Rimiducid
External IDs
  • AP 1903
  • AP-1903
  • AP1903

Pharmacology

Indication

Investigated for use/treatment in bone marrow transplant and graft versus host disease.

Pharmacology
Reduce drug development failure rates
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Contraindications & Blackbox Warnings
Contraindications
Avoid life-threatening adverse drug events
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Pharmacodynamics

Rimiducis is used to activate inducible caspase-9 produced by a modified gene included in some CAR T-cell therapies.2,3 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.4

Mechanism of action

Rimiducid binds to a drug binding domain derived from human FK506-binding protein which is present on a modified form of inducible caspase-9.2 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.

TargetActionsOrganism
USerine/threonine-protein kinase mTOR
ligand
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
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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
Classification
Not classified
Affected organisms
Not Available

Chemical Identifiers

UNII
H564L1W5J2
CAS number
195514-63-7
InChI Key
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
IUPAC Name
(1R)-3-(3,4-dimethoxyphenyl)-1-[3-({[2-(2-{3-[(1R)-3-(3,4-dimethoxyphenyl)-1-[(2S)-1-[(2S)-2-(3,4,5-trimethoxyphenyl)butanoyl]piperidine-2-carbonyloxy]propyl]phenoxy}acetamido)ethyl]carbamoyl}methoxy)phenyl]propyl (2S)-1-[(2S)-2-(3,4,5-trimethoxyphenyl)butanoyl]piperidine-2-carboxylate
SMILES
CC[C@H](C(=O)N1CCCC[C@H]1C(=O)O[C@H](CCC1=CC=C(OC)C(OC)=C1)C1=CC(OCC(=O)NCCNC(=O)COC2=CC=CC(=C2)[C@@H](CCC2=CC=C(OC)C(OC)=C2)OC(=O)[C@@H]2CCCCN2C(=O)[C@@H](CC)C2=CC(OC)=C(OC)C(OC)=C2)=CC=C1)C1=CC(OC)=C(OC)C(OC)=C1

References

General References
  1. DeRose R, Miyamoto T, Inoue T: Manipulating signaling at will: chemically-inducible dimerization (CID) techniques resolve problems in cell biology. Pflugers Arch. 2013 Mar;465(3):409-17. doi: 10.1007/s00424-012-1208-6. Epub 2013 Jan 9. [Article]
  2. Straathof KC, Pule MA, Yotnda P, Dotti G, Vanin EF, Brenner MK, Heslop HE, Spencer DM, Rooney CM: An inducible caspase 9 safety switch for T-cell therapy. Blood. 2005 Jun 1;105(11):4247-54. doi: 10.1182/blood-2004-11-4564. Epub 2005 Feb 22. [Article]
  3. 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. [Article]
  4. Di Stasi A, Tey SK, Dotti G, Fujita Y, Kennedy-Nasser A, Martinez C, Straathof K, Liu E, Durett AG, Grilley B, Liu H, Cruz CR, Savoldo B, Gee AP, Schindler J, Krance RA, Heslop HE, Spencer DM, Rooney CM, Brenner MK: Inducible apoptosis as a safety switch for adoptive cell therapy. N Engl J Med. 2011 Nov 3;365(18):1673-83. doi: 10.1056/NEJMoa1106152. [Article]
  5. Definition of rimiducid - NCI Drug Dictionary - National Cancer Institute [Link]
  6. Technology - Bellicum Pharmaceuticals, Inc. [Link]
PubChem Substance
347909868
ChemSpider
17292138
ChEMBL
CHEMBL269259

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2Active Not RecruitingTreatmentAcute Lymphoblastic Leukemia (ALL) / Aplastic Anemia / Congenital Hypoplastic Anemia / Cytopenias / Haemoglobinopathies congenital / Leukemia, Acute Myeloid (AML), Child / Myelodysplastic Syndromes (MDS) / Non-Hodgkin's Lymphoma (NHL) / Osteopetrosis / Primary Immunodeficiencies (PID) / Sickle Cell Anemia / Thalassaemic disorders1
2, 3TerminatedTreatmentAcute Myeloid Leukemia (AML) / Myelodysplastic Syndromes (MDS)1
1Active Not RecruitingTreatmentAcute Lymphoblastic Leukemia (ALL) / Acute Myeloid Leukemia (AML) / Epstein Barr Virus Infections / Familial Hemophagocytic Lymphohistiocytosis (FLH) / Hemophagocytic Lymphohistiocytosis / Hemophagocytic Syndrome (HPS) / Leukemia Chronic Myelogenous Leukemia (CML) / Myelodysplastic Syndromes (MDS) / Non-Hodgkin's Lymphoma (NHL) / X-linked Lymphoproliferative Disease (XLP)1
1Active Not RecruitingTreatmentBreast Cancer / Metastatic HER2-negative Breast1
1Active Not RecruitingTreatmentHaemoglobinopathies congenital / Hemophagocytic Lymphohistiocytosis / Inherited Bone Marrow Failure Syndromes / Metabolic Disorders / Primary Immune Deficiency Disorders (PIDD)1
1Active Not RecruitingTreatmentLeukemias / Malignant Lymphomas / Multiple Myeloma (MM) / Myelodysplastic Syndromes (MDS) / Neoplasms, Hematologic1
1Active Not RecruitingTreatmentMalignancies, Hematologic1
1CompletedTreatmentCastration Resistant Prostate Cancer2
1CompletedTreatmentMalignant Melanoma of Skin / Neuroblastoma (NB) / Sarcoma, Osteogenic / Sarcomas1
1CompletedTreatmentMultiple Myeloma (MM) / Plasma Cell Myeloma1

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 Solubility0.000397 mg/mLALOGPS
logP6.88ALOGPS
logP10.06ChemAxon
logS-6.6ALOGPS
pKa (Strongest Acidic)14.34ChemAxon
pKa (Strongest Basic)-1.2ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count18ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area262.18 Å2ChemAxon
Rotatable Bond Count39ChemAxon
Refractivity379.49 m3·mol-1ChemAxon
Polarizability153.98 Å3ChemAxon
Number of Rings8ChemAxon
Bioavailability0ChemAxon
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
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Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Ligand
General Function
Tfiiic-class transcription factor binding
Specific Function
Serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals. MTOR directly...
Gene Name
MTOR
Uniprot ID
P42345
Uniprot Name
Serine/threonine-protein kinase mTOR
Molecular Weight
288889.05 Da

Drug created on October 21, 2007 22:23 / Updated on February 21, 2021 18:51