A8764-5mg | Rapalink-1 Clinisciences

Background

RapaLink-1 is the third-generation mTOR inhibitor exploiting the unique juxtaposition of two drug (first- and second- generation mTOR kinase inhibitors) -binding pockets to create a bivalent interaction that allows inhibition of the mutants which has resistance to the previous TORKi (mTOR kinase inhibitors).

The PIK3CA-AKT-mTOR pathway is one of the most commonly activated pathways in human cancers, which has led to the development of small-molecule inhibitors that target various nodes in the pathway. Two generation of mTOR inhibitor had been developed.

Rapalink-1 is more potent than first- and second- generation mTOR inhibitors. RapaLink-1 could more potently reduce levels of both p-4EBP1 and cell proliferation. Researches compared rapamycin, RapaLink-1, and MLN0128 in LN229 and U87MG. Both growth inhibition and arrest in G0/G1 were more potent in response to RapaLink-1, compared with rapamycin or MLN0128. RapaLink-1 shows potent anti-tumor efficacy in vivo. RapaLink-1 led to initial regression and subsequent stabilization of tumor size in a xenograft model, while tumors treated with vehicle, rapamycin, or MLN0128 grew steadily.

RapaLink-1 could durably block mTORC1. RapaLink-1 is associated with FKBP12, an abundant mTOR-interacting protein, enabling accumulation of RapaLink-1. RapaLink-1 showed better efficacy than rapamycin or TORKi, potently blocking cancer-derived, activating mutants of mTOR.

References:
[1] Fan Q1, Aksoy O1, Wong RA1, et al., A Kinase Inhibitor Targeted to mTORC1 Drives Regression in Glioblastoma. Cancer Cell. 2017 Mar 13; 31 (3): 424-435. doi: 10.1016/j.ccell.2017.01.014.
[2] Rodrik-Outmezguine VS1, Okaniwa M2, Yao Z1, et al., Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor. Nature. 2016 Jun 9; 534 (7606): 272-6. doi: 10.1038/nature17963. Epub 2016 May 18.

Product Citation

1. Erin M O'Leary, Yufeng Tian, et al. "TGF-β Promotes Metabolic Reprogramming in Lung Fibroblasts via mTORC1-dependent ATF4 Activation." Am J Respir Cell Mol Biol. 2020 Nov;63(5):601-612. PMID:32668192
2. Kuroshima K, Yoshino H, et al. "Potential new therapy of Rapalink-1, a new generation mammalian target of rapamycin inhibitor, against sunitinib-resistant renal cell carcinoma." Cancer Sci. 2020;111(5):1607-1618. PMID:32232883

Chemical Properties

Storage	Store at -20°C
M.Wt	1784.14
Formula	C₉₁H₁₃₈N₁₂O₂₄
Solubility	≥178.4 mg/mL in DMSO; insoluble in H2O; ≥24.85 mg/mL in EtOH
SDF	Download SDF
Canonical SMILES	O=C(NCCCCN1N=C(C2=CC=C(OC(N)=N3)C3=C2)C4=C(N)N=CN=C41)CCOCCOCCOCCOCCOCCOCCOCCOCCN5C=C(COCCO[C@@H]6CC[C@@H](C[C@H]([C@@H](OC([C@H](CCCC7)N7C(C([C@@]8(O)[C@H](C)CC[C@H](O8)C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C([C@H](OC)[C@H](O)/C(C)=C/[C@H]9C)=O)=O
Shipping Condition	Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice.
General tips	We do not recommend long-term storage for the solution, please use it up soon.

Protocol

Cell experiment:[1]
Cell lines	Human glioma cell line U87MG
Reaction Conditions	0 ~ 200 nM Rapalink-1 for 3 days
Applications	In U87MG cells, both growth inhibition (0 ~ 200 nM Rapalink-1; 3 days) and arrest in G0/G1 (0 ~ 12.5 nM Rapalink-1; 48 hours) were more obvious in response to Rapalink-1, compared with Rapamycin or MLN0128.
Animal experiment:[1]
Animal models	BALB/C^nu/nu mice bearing U87MG intracranial xenografts
Dosage form	1.5 mg/kg Injected intraperitoneally (i.p.) every 5 or 7 days
Applications	Rapalink-1 led to initial regression and subsequent stabilization of tumor size, while tumors treated with vehicle, Rapamycin, or MLN0128 grew steadily. Furthermore, Rapalink-1 was well tolerated and associated with significantly improved survival.
Note	The technical data provided above is for reference only.
	References: 1. Fan Q, Aksoy O, Wong RA, et al. A kinase inhibitor targeted to mTORC1 drives regression in glioblastoma. Cancer Cell, 2017, 31(3): 424-435.