Pralsetinib Chemical Properties

Boiling point:

799.1±60.0 °C(Predicted)

Density 

1.40±0.1 g/cm3(Predicted)

storage temp. 

Store at 4°C

solubility 

DMSO : ≥ 100 mg/mL (187.41 mM);Water : < 0.1 mg/mL (insoluble)

form 

Solid

pka

14.33±0.10(Predicted)

color 

White to off-white

InChIKey

GBLBJPZSROAGMF-BATDWUPUSA-N

SMILES

[C@]1(OC)(C(N[C@H](C2=CC=C(N3C=C(F)C=N3)N=C2)C)=O)CC[C@H](C2=NC(NC3C=C(C)NN=3)=CC(C)=N2)CC1

Pralsetinib Usage And Synthesis

Binding Mode

In the co-crystal structure of pralsetinib in complex with RET kinase (Fig. 1), the aminopyrimidinyl and methylaminopyrazolyl subunits fit into the adenosine pocket, forming three critical hydrogen bonds with hinge residues Ala807 and Glu805. In addition, one pyrimidine nitrogen, methoxy oxygen, and one fluoropyrazole nitrogen also interact with the kinase residues indirectly via three bound water molecules (Fig. 2).

Description

Pralsetinib is a potent, selective RET inhibitor, and was optimized from a hit compound identified from a compound library that included more than 60 chemical scaffolds. However, as of 2020, detailed medicinal chemistry on the optimization process has yet to be published. Pralsetinib proved to be more potent and selective than cabozantinib or vandertanib against both wild-type and abnormal RET. The agent also showed a level of selectivity against RET relative to VEGFR2, whereas previous agents showed very little selectivity. On September 4, 2020, the Food and Drug Administration granted accelerated approval to pralsetinib (GAVRETO®, Blueprint Medicines Corporation) for adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC) as detected by an FDA-approved test.

Uses

Pralsetinib is a highly potent and selective RET inhibitor designed for RET-driven cancers.

Indications

Pralsetinib is the second selective RET inhibitor approved by the FDA (following Lilly's selpercatinib) for the treatment of adult patients with metastatic RET (rearranged during transfection) fusion-positive non-small cell lung cancer (NSCLC); (2) adult and pediatric patients >=12 years of age with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy; and (3) adult and pediatric patients >=12 years of age with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory.

brand name

Gavreto

Synthesis Reference(s)

[1] GAIKWAD RAJENDRA. Green One-Pot Chemo-Enzymatic Synthesis of a Key Chiral Amine Intermediate: Useful to Pralsetinib Synthesis[J]. ChemistrySelect, 2023. DOI:10.1002/slct.202204409.
[2] HUGHES* D L. Review of Synthetic Routes and Crystalline Forms of the Oncology Drugs Capmatinib, Selpercatinib, and Pralsetinib[J]. Organic Process Research &amp; Development, 2021. DOI:10.1021/acs.oprd.1c00282.

General Description

Class: receptor tyrosine kinase; Treatment: RET-altered lung, thyroid cancers; Other name: BLU-667; Elimination half-life = 22 h; Protein binding = 97%

Side effects

Pralsetinib may cause side effects: Nausea, vomiting, loss of appetite, diarrhea, constipation, extreme tiredness, dizziness, weakness, night sweats, rapid heartbeat, heartburn, shortness of breath, headache, sores in the mouth, confusion, changes in vision, fever, cough, chills, nosebleeds, pale skin, rash, itching, hives, weight changes, hair loss, back pain, muscle pain, joint pain, bone pain, unusual bruising or bleeding, blood in the urine or stool, bloody or black tarry stools, difficulty falling asleep or staying asleep, unusual vaginal bleeding, and other less common effects.

target

Primary target: RET

Mode of action

Kinase inhibitor of wild-type RET, oncogenic RET fusions, and select mutations. Pralsetinib may also inhibit other pathways including those through FLT3, JAK1-2, PDGFRB, VEGFR-2, and FGFR1. RET fusion proteins and activating point mutations can act as oncogenic drivers by promoting cell proliferation of tumor cell lines and pralsetinib inhibits this process.

Pralsetinib(2097132-94-8)Related Product Information

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