Drug Information

Drug (ID: DG01307) and It's Reported Resistant Information

• Name: Pralsetinib
• Synonyms: Pralsetinib; BLU-667; 2097132-94-8; Pralsetinib free base; cis-Pralsetinib; Blu667; trans-Pralsetinib; UNII-1WPE73O1WV; 1WPE73O1WV; BLU123244; 2097132-94-8 (free base); 2097132-93-7; N-[(1S)-1-[6-(4-fluoropyrazol-1-yl)pyridin-3-yl]ethyl]-1-methoxy-4-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]cyclohexane-1-carboxamide; X581238; cis-N-{(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl}-1-methoxy-4-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}cyclohexane-1-carboxamide; Gavreto; Cyclohexanecarboxamide, N-((1S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)-3-pyridinyl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)-2-pyrimidinyl)-, cis-; cyclohexanecarboxamide, N-[(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)-3-pyridinyl]ethyl]-1-methoxy-4-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]-, cis-; Q4J; Pralsetinib [INN]; Pralsetinib [USAN]; Blu667Blu667; cis-BLU-667; Pralsetinib (USAN/INN); BLU-667 (Pralsetinib); CHEMBL4582651; SCHEMBL18789228; SCHEMBL18789229; SCHEMBL18806610; GTPL10033; BDBM435009; BDBM435010; AMY16875; EX-A1944; EX-A3347; NSC811429; s8716; US10584114, Compound 129; US10584114, Compound 130; WHO 11004; AKOS037648884; BLU-123244; HY-112301A; NSC-811429; BS-15942; HY-112301; CS-0043448; CS-0044766; D11712; X-581238; (cis)-N-((S)-1-(6-(4-Fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexanecarboxamide; BLU-667; trans-N-{(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl}-1-methoxy-4-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}cyclohexane-1-carboxamide; trans-N-{(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl}-1-methoxy-4-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}cyclohexane-1-carboxamide
• Indication:
  In total 2 Indication(s)
  Non-small-cell lung cancer [ICD-11: 2C25]; Approved; [1]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; 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: C27H32FN9O2
• IsoSMILES: CC1=CC(=NN1)NC2=NC(=NC(=C2)C)C3CCC(CC3)(C(=O)N[C@@H](C)C4=CN=C(C=C4)N5C=C(C=N5)F)OC
• InChI: 1S/C27H32FN9O2/c1-16-11-22(33-23-12-17(2)35-36-23)34-25(31-16)19-7-9-27(39-4,10-8-19)26(38)32-18(3)20-5-6-24(29-13-20)37-15-21(28)14-30-37/h5-6,11-15,18-19H,7-10H2,1-4H3,(H,32,38)(H2,31,33,34,35,36)/t18-,19 ,27 /m0/s1
• InChIKey: GBLBJPZSROAGMF-SIYOEGHHSA-N
• PubChem CID: 129073603
• TTD Drug ID: D0OD2I

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

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.

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) [2]

• 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: TPC-1 cells; Thyroid; Homo sapiens (Human); CVCL_6298
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: TT cells; Thyroid gland; Homo sapiens (Human); CVCL_1774
• In Vitro Model: MZ-CRC-1 cells; Pleural effusion; Homo sapiens (Human); CVCL_A656
• In Vitro Model: LC2/ad cells; Pleural effusion; Homo sapiens (Human); CVCL_1373
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Promega assay

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

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.C634W (c.1902C>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: TPC-1 cells; Thyroid; Homo sapiens (Human); CVCL_6298
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: TT cells; Thyroid gland; Homo sapiens (Human); CVCL_1774
• In Vitro Model: MZ-CRC-1 cells; Pleural effusion; Homo sapiens (Human); CVCL_A656
• In Vitro Model: LC2/ad cells; Pleural effusion; Homo sapiens (Human); CVCL_1373
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Promega assay

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: Precision Targeted Therapy with BLU-667 for RET-Driven CancersCancer Discov. 2018 Jul;8(7):836-849. doi: 10.1158/2159-8290.CD-18-0338. Epub 2018 Apr 15.