Drug Information

Drug (ID: DG01309) and It's Reported Resistant Information

• Name: Selpercatinib
• Synonyms: Selpercatinib; 2152628-33-4; LOXO-292; CEGM9YBNGD; UNII-CEGM9YBNGD; LOXO292; 6-(2-hydroxy-2-methylpropoxy)-4-[6-[6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]pyridin-3-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; LY3527723; 6-(2-Hydroxy-2-methylpropoxy)-4-[6-[6-[(6-methoxy-3-pyridinyl)methyl]-3,6-diazabicyclo[3.1.1]hept-3-yl]-3-pyridinyl]pyrazolo[1,5-a]pyridine-3-carbonitrile; Serpercatinib; Retevmo; 6-(2-Hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo(3.1.1)heptan-3-yl)pyridin-3-yl)pyrazolo(1,5-a)pyridine-3-carbonitrile; Retevmo (TN); Selpercatinib [INN]; Selpercatinib [USAN]; Ret inhibitor loxo-292; LOXO-292; Selpercatinib; Selpercatinib(LOXO-292); CHEMBL4559134; SCHEMBL20071478; Selpercatinib (JAN/USAN/INN); GTPL10318; BDBM296429; BCP29047; CLD62833; EX-A2859; NSC818434; s8781; WHO 10967; ZB1574; US10112942, Example 163; US10112942, Example 166; US10112942, Example 183; AKOS037649115; NSC-818434; AC-31588; BS-16622; LOXO-292;LOXO 292;LOXO292; Selpercatinib (LOXO-292, ARRY-192); example 163 [WO2018071447A1]; HY-114370; CS-0084279; LY-3527723; D11713; D77980; A929273; Pyrazolo(1,5-a)pyridine-3-carbonitrile, 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxy-3-pyridinyl)methyl)-3,6-diazabicyclo(3.1.1)hept-3-yl)-3-pyridinyl)-
• Indication:
  In total 3 Indication(s)
  Colon cancer [ICD-11: 2B90]; Approved; [1]
  Non-small-cell lung cancer [ICD-11: 2C25]; Approved; [1]
  Thyroid cancer [ICD-11: 2D10]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
  Lung cancer [ICD-11: 2C25]; [1]
  Thyroid cancer [ICD-11: 2D10]; [1]
• Target: Proto-oncogene c-Ret (RET); RET_HUMAN; [1]
• Formula: C29H31N7O3
• IsoSMILES: CC(C)(COC1=CN2C(=C(C=N2)C#N)C(=C1)C3=CN=C(C=C3)N4CC5CC(C4)N5CC6=CN=C(C=C6)OC)O
• InChI: 1S/C29H31N7O3/c1-29(2,37)18-39-24-9-25(28-21(10-30)13-33-36(28)17-24)20-5-6-26(31-12-20)34-15-22-8-23(16-34)35(22)14-19-4-7-27(38-3)32-11-19/h4-7,9,11-13,17,22-23,37H,8,14-16,18H2,1-3H3
• InChIKey: XIIOFHFUYBLOLW-UHFFFAOYSA-N
• PubChem CID: 134436906
• TTD Drug ID: D01KOA

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [2]

• Molecule Alteration: Missense mutation; p.M918T (c.2753T>C)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vivo Model: mouse PDX model; Mus musculus
• Mechanism Description: LOXO-292 demonstrated potent and selective anti-RET activity preclinically against human cancer cell lines harboring endogenous RET gene alterations.

Lung cancer [ICD-11: 2C25]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [1]

• Molecule Alteration: Mutation; .
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Drug Resistance: Cell-free DNAs (cfDNAs) analysis
• Mechanism Description: Selpercatinib (LOXO-292) and pralsetinib (BLU-667) are highly potent RET-selective protein tyrosine kinase inhibitors (TKIs) for treating advanced RET-altered thyroid cancers and non-small-cell lung cancer (NSCLC). RET mutations at the solvent front and the hinge are resistant to both drugs. Selpercatinib and pralsetinib use an unconventional mode to bind RET that avoids the interference from gatekeeper mutations but is vulnerable to non-gatekeeper mutations.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [3]

• Molecule Alteration: Other; .
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data

Thyroid cancer [ICD-11: 2D10]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [1]

• Molecule Alteration: Mutation; .
• Resistant Disease: Advanced RET-altered thyroid cancer [ICD-11: 2D10.Y]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Drug Resistance: Cell-free DNAs (cfDNAs) analysis
• Mechanism Description: Selpercatinib (LOXO-292) and pralsetinib (BLU-667) are highly potent RET-selective protein tyrosine kinase inhibitors (TKIs) for treating advanced RET-altered thyroid cancers and non-small-cell lung cancer (NSCLC). RET mutations at the solvent front and the hinge are resistant to both drugs. Selpercatinib and pralsetinib use an unconventional mode to bind RET that avoids the interference from gatekeeper mutations but is vulnerable to non-gatekeeper mutations.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [2]

• Molecule Alteration: Missense mutation; p.M918T (c.2753T>C)
• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vivo Model: mouse PDX model; Mus musculus
• Mechanism Description: LOXO-292 demonstrated potent and selective anti-RET activity preclinically against human cancer cell lines harboring endogenous RET gene alterations.

References

• Ref 1: Structural basis of acquired resistance to selpercatinib and pralsetinib mediated by non-gatekeeper RET mutations .Ann Oncol. 2021 Feb;32(2):261-268. doi: 10.1016/j.annonc.2020.10.599. Epub 2020 Nov 5. 10.1016/j.annonc.2020.10.599
• Ref 2: Selective RET kinase inhibition for patients with RET-altered cancersAnn Oncol. 2018 Aug 1;29(8):1869-1876. doi: 10.1093/annonc/mdy137.
• Ref 3: Efficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung CancerN Engl J Med. 2020 Aug 27;383(9):813-824. doi: 10.1056/NEJMoa2005653.