Pacritinib

Pacritinib (INN[1]) is a macrocyclic Janus kinase inhibitor that is being developed for the treatment of myelofibrosis. It mainly inhibits Janus kinase 2 (JAK2) and Fms-like tyrosine kinase 3 (FLT3). The drug was in Phase III clinical trials as of 2013.[2] The drug was discovered in Singapore at the labs of S*BIO Pte Ltd. It is a potent JAK2 inhibitor with activity of IC50 = 23 nM for the JAK2WT variant and 19 nM for JAK2V617F with very good selectivity against JAK1 and JAK3 (IC50 = 1280 and 520 nM, respectively).[3][4]

Pacritinib
Clinical data
Other namesSB1518
Routes of
administration		Oral
ATC code
  • None
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC28H32N4O3
Molar mass472.589 g·mol−1
3D model (JSmol)

The drug was acquired by Cell Therapeutics, Inc. (CTI) and Baxter International and could effectively address an unmet medical need for patients living with myelofibrosis who face treatment-emergent thrombocytopenia on marketed JAK inhibitors.[5] When Shire Pharmaceuticals purchased Baxalta, a spin-off of Baxter Pharmaceuticals, they halted the development of the drug and ended their partnership with CTI.[6][7]

The drug was given fast-track status in 2014.[8] In 2016, the FDA placed a full clinical hold on pacritinib due to concerns about increased mortality in patients receiving the drug in the "PERSIST-2" trial.[9] The clinical hold was lifted in January 2017.[10]

References
  1. "International Nonproprietary Names for Pharmaceutical Substances (INN) List 104" (PDF). WHO Drug Information. 24 (4): 386. 2010.
  2. "JAK-Inhibitoren: Neue Wirkstoffe für viele Indikationen". Pharmazeutische Zeitung (in German) (21). 2013.
  3. William AD, Lee AC, Blanchard S, Poulsen A, Teo EL, Nagaraj H, et al. (July 2011). "Discovery of the macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a potent Janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor for the treatment of myelofibrosis and lymphoma". Journal of Medicinal Chemistry. 54 (13): 4638–58. doi:10.1021/jm200326p. PMID 21604762.
  4. Poulsen A, William A, Blanchard S, Lee A, Nagaraj H, Wang H, et al. (April 2012). "Structure-based design of oxygen-linked macrocyclic kinase inhibitors: discovery of SB1518 and SB1578, potent inhibitors of Janus kinase 2 (JAK2) and Fms-like tyrosine kinase-3 (FLT3)". Journal of Computer-Aided Molecular Design. 26 (4): 437–50. Bibcode:2012JCAMD..26..437P. doi:10.1007/s10822-012-9572-z. PMID 22527961.
  5. "Baxter licenses cancer drug from CTI in $172m deal". PMLiVE. 2013-11-18.
  6. "Pacritinib". CTI BioPharma Corp.
  7. "Shire ends pacritinib development deal with CTI post Baxalta merger". in-PharmaTechnologist. William Reed Business Media Ltd.
  8. Adams B (29 August 2016). "Struggling CTI reveals new pacritinib data, misses a primary endpoint". Fierce Biotech.
  9. "CTI BioPharma's (CTIC) Pacritinib Placed on Full Clinical Hold; NDA Withdrawn". StreetInsider. 10 February 2016.
  10. "CTI BioPharma Announces Removal Of Full Clinical Hold On Pacritinib". PR Newswire. Retrieved 18 April 2017.
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