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]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Unspecified malignant neoplasms of unspecified sites [ICD-11: 2D4Z]; [2]
• 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) [3]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.M918T (c.2753T>C)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.64 Å; PDB: 7DUA
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 2.12 Å; PDB: 4CKI

RMSD: 0.93; TM score: 0.95555; Amino acid change: M918T

• 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]

• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Molecule Alteration: Mutation; .
• 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) [4]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Other; .
• 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]

• Resistant Disease: Advanced RET-altered thyroid cancer [ICD-11: 2D10.Y]
• Molecule Alteration: Mutation; .
• 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) [3]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.M918T (c.2753T>C)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.64 Å; PDB: 7DUA
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 2.12 Å; PDB: 4CKI

RMSD: 0.93; TM score: 0.95555; Amino acid change: M918T

• 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.

Unspecified malignant neoplasms of unspecified sites [ICD-11: 2D4Z]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Receptor tyrosine-protein kinase erbB-3 (ERBB3) [2]

• Resistant Disease: ret-aberrant cancers [ICD-11: 2D4Z]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: YAP-HER3 signaling pathway; Regulation; N.A.
• In Vitro Model: LC2/ad cells; Pleural effusion; Homo sapiens (Human); CVCL_1373
• In Vitro Model: TPC-1 cells; Thyroid; Homo sapiens (Human); CVCL_6298
• In Vitro Model: TT cells; Thyroid gland; Homo sapiens (Human); CVCL_1774
• In Vivo Model: Severe combined immunodeficiency mice model; Mus musculus
• Experiment for Molecule Alteration: Western blot assay; RT-PCR; RNA sequencing assay; Phospho-receptor tyrosine kinase antibody arrays assay; Chromatin immunoprecipitation assay; Luciferase reporter assay
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: In high YAP-expressing RET-aberrant cancer cells, YAP-mediated HER3 signaling activation maintained cell survival and induced the emergence of cells tolerant to the RET-TKIs selpercatinib and pralsetinib. The pan-ErBB inhibitor afatinib and YAP/tea domain inhibitors verteporfin and K-975 sensitized YAP-expressing RET-aberrant cancer cells to the RET-TKIs selpercatinib and pralsetinib. Pretreatment YAP expression in clinical specimens obtained from patients with RET fusion-positive lung cancer was associated with poor RET-TKI treatment outcomes.The YAP-HER3 axis is crucial for the survival and adaptive resistance of high YAP-expressing RET-aberrant cancer cells treated with RET-TKIs. Combining YAP/HER3 inhibition with RET-TKIs represents a highly potent strategy for initial treatment.

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: YAP Regulates HER3 Signaling-Driven Adaptive Resistance to RET Inhibitors in RET-Aberrant Cancers. Clin Cancer Res. 2025 Mar 17;31(6):1127-1141.
• Ref 3: Selective RET kinase inhibition for patients with RET-altered cancersAnn Oncol. 2018 Aug 1;29(8):1869-1876. doi: 10.1093/annonc/mdy137.
• Ref 4: 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.