Linsitinib

Linsitinib
Names

Preferred IUPAC name (1s,3s)-3-[8-Amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclobutan-1-ol
Other names OSI-906
Identifiers
CAS Number	867160-71-2^Y
3D model (JSmol)	Interactive image
ChEBI	CHEBI:91402
ChEMBL	ChEMBL1091644
ChemSpider	21391708
DrugBank	DB06075
KEGG	D09925
PubChem CID	11640390
UNII	15A52GPT8T
CompTox Dashboard (EPA)	DTXSID401007055
InChI InChI=1S/C26H23N5O/c1-26(32)14-19(15-26)25-30-22(23-24(27)28-11-12-31(23)25)18-8-7-17-9-10-20(29-21(17)13-18)16-5-3-2-4-6-16/h2-13,19,32H,14-15H2,1H3,(H2,27,28) Key: PKCDDUHJAFVJJB-UHFFFAOYSA-N InChI=1/C26H23N5O/c1-26(32)14-19(15-26)25-30-22(23-24(27)28-11-12-31(23)25)18-8-7-17-9-10-20(29-21(17)13-18)16-5-3-2-4-6-16/h2-13,19,32H,14-15H2,1H3,(H2,27,28)/t19-,26+ Key: PKCDDUHJAFVJJB-VLZXCDOPBI
SMILES C[C@]1(C[C@@H](C1)C2=NC(=C3N2C=CN=C3N)C4=CC5=C(C=CC(=N5)C6=CC=CC=C6)C=C4)O
Properties
Chemical formula	C₂₆H₂₃N₅O
Molar mass	421.504 g·mol⁻¹
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Infobox references

Chemical compound

Linsitinib is an experimental drug candidate for the treatment of various types of cancer. It is an inhibitor of the insulin receptor and of the insulin-like growth factor 1 receptor (IGF-1R).^[1] This prevents tumor cell proliferation and induces tumor cell apoptosis.^[2]

Linsitinib was granted orphan drug designation for adrenocortical carcinoma in March 2012.^[3]

Phase II clinical trials were initiated for multiple myeloma, ovarian cancer, hepatocellular carcinoma, and NSCLC, but subsatisfactory results caused research for these indications to be discontinued.^[3] A phase III clinical trial found that linsitinib did not increase survival in patients with adrenocortical carcinoma.^[4] As of 2017, no clinical trials were in progress.^[3]

References

^ Mulvihill, Mark J; Cooke, Andrew; Rosenfeld-Franklin, Maryland; Buck, Elizabeth; Foreman, Ken; Landfair, Darla; O’Connor, Matthew; Pirritt, Caroline; Sun, Yingchaun; Yao, Yan; Arnold, Lee D; Gibson, Neil W; Ji, Qun-Sheng (September 2009). "Discovery of OSI-906: a selective and orally efficacious dual inhibitor of the IGF-1 receptor and insulin receptor". Future Medicinal Chemistry. 1 (6): 1153–1171. doi:10.4155/fmc.09.89. PMID 21425998.
^ "Linsitinib". NCI Drug Dictionary. National Cancer Institute. Retrieved October 16, 2012.
^ ^a ^b ^c "Linsitinib - AdisInsight". adisinsight.springer.com.
^ Fassnacht, Martin; Berruti, Alfredo; Baudin, Eric; Demeure, Michael J; Gilbert, Jill; Haak, Harm; Kroiss, Matthias; Quinn, David I; Hesseltine, Elizabeth; Ronchi, Cristina L; Terzolo, Massimo; Toni Choueiri; Poondru, Srinivasu; Fleege, Tanya; Rorig, Ramona; Chen, Jihong; Stephens, Andrew W; Worden, Francis; Hammer, Gary D (April 2015). "Linsitinib (OSI-906) versus placebo for patients with locally advanced or metastatic adrenocortical carcinoma: a double-blind, randomised, phase 3 study". The Lancet Oncology. 16 (4): 426–435. doi:10.1016/S1470-2045(15)70081-1. hdl:2318/1534804. PMID 25795408.

External links

Media related to Linsitinib at Wikimedia Commons

Growth factor receptor modulators

Angiopoietin

Agonists: Angiopoietin 1
Angiopoietin 4

Antagonists: Angiopoietin 2
Angiopoietin 3

Kinase inhibitors: Altiratinib
CE-245677
Rebastinib

Antibodies: Evinacumab (against angiopoietin 3)
Nesvacumab (against angiopoietin 2)

CNTF

Agonists: Axokine
CNTF
Dapiclermin

EGF (ErbB)

EGF (ErbB1/HER1)	Agonists: Amphiregulin Betacellulin EGF (urogastrone) Epigen Epiregulin Heparin-binding EGF-like growth factor (HB-EGF) Murodermin Nepidermin Transforming growth factor alpha (TGFα) Kinase inhibitors: Afatinib Agerafenib Brigatinib Canertinib Dacomitinib Erlotinib Gefitinib Grandinin Icotinib Lapatinib Neratinib Osimertinib Vandetanib WHI-P 154 Antibodies: Cetuximab Depatuxizumab Depatuxizumab mafodotin Futuximab Imgatuzumab Matuzumab Necitumumab Nimotuzumab Panitumumab Zalutumumab
ErbB2/HER2	Agonists: Unknown/none Antibodies: Ertumaxomab Pertuzumab Trastuzumab Trastuzumab deruxtecan Trastuzumab duocarmazine Trastuzumab emtansine Kinase inhibitors: Afatinib Lapatinib Mubritinib Neratinib Tucatinib
ErbB3/HER3	Agonists: Neuregulins (heregulins) (1, 2, 6 (neuroglycan C)) Antibodies: Duligotumab Patritumab Seribantumab
ErbB4/HER4	Agonists: Betacellulin Epigen Heparin-binding EGF-like growth factor (HB-EGF) Neuregulins (heregulins) (1, 2, 3, 4, 5 (tomoregulin, TMEFF))

FGF

FGFR1	Agonists: Ersofermin FGF (1, 2 (bFGF), 3, 4, 5, 6, 8, 10 (KGF2), 20) Repifermin Selpercatinib Trafermin Velafermin
FGFR2	Agonists: Ersofermin FGF (1, 2 (bFGF), 3, 4, 5, 6, 7 (KGF), 8, 9, 10 (KGF2), 17, 18, 22) Palifermin Repifermin Selpercatinib Sprifermin Trafermin Antibodies: Aprutumab Aprutumab ixadotin Kinase inhibitors: Infigratinib
FGFR3	Agonists: Ersofermin FGF (1, 2 (bFGF), 4, 8, 9, 18, 23) Selpercatinib Sprifermin Trafermin Antibodies: Burosumab (against FGF23)
FGFR4	Agonists: Ersofermin FGF (1, 2 (bFGF), 4, 6, 8, 9, 19) Trafermin
Unsorted	Agonists: FGF15/19

HGF (c-Met)

Agonists: Fosgonimeton
Hepatocyte growth factor

Potentiators: Dihexa (PNB-0408)

Kinase inhibitors: Altiratinib
AM7
AMG-458
Amuvatinib
BMS-777607
Cabozantinib
Capmatinib
Crizotinib
Foretinib
Golvatinib
INCB28060
JNJ-38877605
K252a
MK-2461
PF-04217903
PF-2341066
PHA-665752
SU-11274
Tivantinib
Volitinib

IGF

IGF-1	Agonists: des(1-3)IGF-1 Insulin-like growth factor-1 (somatomedin C) IGF-1 LR3 Insulin-like growth factor-2 (somatomedin A) Insulin Mecasermin Mecasermin rinfabate Kinase inhibitors: BMS-754807 Linsitinib NVP-ADW742 NVP-AEW541 OSl-906 Antibodies: AVE-1642 Cixutumumab Dalotuzumab Figitumumab Ganitumab Robatumumab R1507 Teprotumumab Xentuzumab (against IGF-1 and IGF-2)
IGF-2	Agonists: Insulin-like growth factor-2 (somatomedin A) Antibodies: Dusigitumab Xentuzumab (against IGF-1 and IGF-2)
Others	Binding proteins: IGFBP (1, 2, 3, 4, 5, 6, 7) Cleavage products/derivatives with unknown target: Glypromate (GPE, (1-3)IGF-1) Trofinetide

LNGF (p75^NTR)

Antagonists: ALE-0540
Dexamethasone
EVT-901 (SAR-127963)
Testosterone

Antibodies: Against NGF: ABT-110 (PG110)
ASP-6294
Fasinumab
Frunevetmab
Fulranumab
MEDI-578
Ranevetmab
Tanezumab

Aptamers: Against NGF: RBM-004

Decoy receptors: LEVI-04 (p75^NTR-Fc)

PDGF

Agonists: Becaplermin
Platelet-derived growth factor (A, B, C, D)

RET (GFL)

GFRα1	Agonists: Glial cell line-derived neurotrophic factor (GDNF) Liatermin Kinase inhibitors: Vandetanib
GFRα2	Agonists: Neurturin (NRTN) Kinase inhibitors: Vandetanib
GFRα3	Agonists: Artemin (ARTN) Kinase inhibitors: Vandetanib
GFRα4	Agonists: Persephin (PSPN) Kinase inhibitors: Vandetanib
Unsorted	Kinase inhibitors: Agerafenib

SCF (c-Kit)

Agonists: Ancestim
Stem cell factor

TGFβ

See here instead.

Trk

TrkA	Agonists: Amitriptyline BNN-20 BNN-27 Cenegermin DHEA DHEA-S Gambogic amide NGF Tavilermide Antagonists: ALE-0540 Dexamethasone FX007 Testosterone Negative allosteric modulators: VM-902A Kinase inhibitors: Altiratinib AZD-6918 CE-245677 CH-7057288 DS-6051 Entrectinib GZ-389988 K252a Larotrectinib Lestaurtinib Milciclib ONO-4474 ONO-5390556 PLX-7486 Rebastinib SNA-120 (pegylated K252a)) Antibodies: Against TrkA: GBR-900; Against NGF: ABT-110 (PG110) ASP-6294 Fasinumab Frunevetmab Fulranumab MEDI-578 Ranevetmab Tanezumab Aptamers: Against NGF: RBM-004 Decoy receptors: ReN-1820 (TrkAd5)
TrkB	Agonists: 3,7-DHF 3,7,8,2'-THF 4'-DMA-7,8-DHF 7,3'-DHF 7,8-DHF 7,8,2'-THF 7,8,3'-THF Amitriptyline BDNF BNN-20 Deoxygedunin Deprenyl Diosmetin DMAQ-B1 HIOC LM22A-4 N-Acetylserotonin NT-3 NT-4 Norwogonin (5,7,8-THF) R7 R13 TDP6 Antagonists: ANA-12 Cyclotraxin B Gossypetin (3,5,7,8,3',4'-HHF) Ligands: DHEA Kinase inhibitors: Altiratinib AZD-6918 CE-245677 CH-7057288 DS-6051 Entrectinib GZ-389988 K252a Larotrectinib Lestaurtinib ONO-4474 ONO-5390556 PLX-7486
TrkC	Agonists: BNN-20 DHEA NT-3 Kinase inhibitors: Altiratinib AZD-6918 CE-245677 CH-7057288 DS-6051 Entrectinib GZ-389988 K252a Larotrectinib Lestaurtinib ONO-4474 ONO-5390556 PLX-7486