RapaLink-1   Click here for help

GtoPdb Ligand ID: 9212

Synonyms: 40-O-(2-((1-(32-(4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-27-oxo-3,6,9,12,15,18,21,24-octaoxa-28-azadotriacontyl)-1H-1,2,3-triazol-4-yl)methoxy)ethyl)-rapamycin
Compound class: Synthetic organic
Comment: RapaLink-1 is a new-generation bivalent (bitopic) mTOR inhibitor, comprising a rapamycin-FRB-binding element (sirolimus, a.k.a. rapamycin) linked to an ATP binding site competitive TORKi (sapanisertib, a.k.a. MLN0128) via a PEG linker [1]. RapaLink-1 is able to overcome resistance to TORKis of mutant mTOR proteins in vitro, inhibiting proliferation MCF-7 cells at levels comparable to rapamycin or a combination of rapamycin and MLN0128.
2D Structure
Click here for help

2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

✖
Click here for structure editor
Physico-chemical Properties
Click here for help

Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

✖
Hydrogen bond acceptors 33
Hydrogen bond donors 5
Rotatable bonds 46
Topological polar surface area 448.98
Molecular weight 1782.99
XLogP 3.64
No. Lipinski's rules broken 2
SMILES / InChI / InChIKey
Click here for help

SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

✖
Canonical SMILES COC1CC(CCC1OCCOCc1nnn(c1)CCOCCOCCOCCOCCOCCOCCOCCOCCC(=O)NCCCCn1nc(c2c1ncnc2N)c1ccc2c(c1)nc(o2)N)CC(C1CC(=O)C(C)C=C(C)C(O)C(OC)C(=O)C(C)CC(C)C=CC=CC=C(C(CC2OC(C(=O)C(=O)N3C(C(=O)O1)CCCC3)(O)C(C)CC2)OC)C)C
Isomeric SMILES CO[C@@H]1C[C@H](CC[C@@H]1OCCOCc1nnn(c1)CCOCCOCCOCCOCCOCCOCCOCCOCCC(=O)NCCCCn1nc(c2c1ncnc2N)c1ccc2c(c1)nc(o2)N)C[C@H]([C@@H]1CC(=O)[C@H](C)/C=C(\C)/[C@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)/C=C/C=C/C=C(/[C@@H](C[C@H]2O[C@](C(=O)C(=O)N3[C@@H](C(=O)O1)CCCC3)(O)[C@H](C)CC2)OC)\C)C
InChI InChI=1S/C91H138N12O24/c1-60-18-12-11-13-19-61(2)76(112-8)55-70-24-21-66(7)91(111,127-70)85(108)88(109)102-29-16-14-20-72(102)89(110)125-77(56-73(104)62(3)51-65(6)83(107)84(114-10)82(106)64(5)50-60)63(4)52-67-22-25-75(78(53-67)113-9)124-49-48-123-58-69-57-101(100-98-69)31-33-116-35-37-118-39-41-120-43-45-122-47-46-121-44-42-119-40-38-117-36-34-115-32-27-79(105)94-28-15-17-30-103-87-80(86(92)95-59-96-87)81(99-103)68-23-26-74-71(54-68)97-90(93)126-74/h11-13,18-19,23,26,51,54,57,59-60,62-64,66-67,70,72,75-78,83-84,107,111H,14-17,20-22,24-25,27-50,52-53,55-56,58H2,1-10H3,(H2,93,97)(H,94,105)(H2,92,95,96)/b13-11+,18-12+,61-19+,65-51+/t60-,62-,63-,64-,66-,67-,70+,72-,75+,76-,77+,78-,83+,84+,91-/m1/s1
InChI Key QDOGZMBPRITPMZ-LFEDRMHTSA-N
Bioactivity Comments
RapaLink-1 shows prolonged inhibition of mTOR signalling in vitro and in vivo, with in vivo antiproliferative effects lasting for over 4 days post-administration. Proof of dual engagement is shown by RapaLink-1's ability to effectively inhibit mTOR activation in cells exogenously expressing FRB (F2108L) and kinase-domain (M2327I) double mutation (using doses of 3-10 nM) [1]. Wild-type cells are also sensitive to RapaLink-1.
Selectivity at enzymes
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
mechanistic target of rapamycin kinase Hs Inhibitor Inhibition - - - 1
⤷ [1]