Bafetinib

Bafetinib

Legal status
Legal status	Investigational
Identifiers
Synonyms	NS-187, INNO-406
CAS Number	859212-16-1
PubChem CID	11387605
ChemSpider	9562515
KEGG	D10202
Chemical and physical data
Formula	C30H31F3N8O
Molar mass	576.63 g·mol−1
3D model (Jmol)	Interactive image
SMILES CC1=C(C=C(C=C1)NC(=O)C2=CC(=C(C=C2)CN3CC[C@@H](C3)N(C)C)C(F)(F)F)NC4=NC=CC(=N4)C5=CN=CN=C5
InChI InChI=1S/C30H31F3N8O/c1-19-4-7-23(13-27(19)39-29-36-10-8-26(38-29)22-14-34-18-35-15-22)37-28(42)20-5-6-21(25(12-20)30(31,32)33)16-41-11-9-24(17-41)40(2)3/h4-8,10,12-15,18,24H,9,11,16-17H2,1-3H3,(H,37,42)(H,36,38,39)/t24-/m0/s1 Key:ZGBAJMQHJDFTQJ-DEOSSOPVSA-N

Bafetinib (NS-187) is an experimental cancer drug developed by Nippon Shinyaku and licensed to CytRx. It is an inhibitor of Lyn and Bcr-Abl. It is currently in phase II clinical trials.

Imatinib was the first Bcr-Abl tyrosine-kinase inhibitor and was highly successful in treatment of chronic myelogenous leukemia, which had previous had no effective treatment. With the emerging resistance to imatinib treatment, alternative treatment was highly sought after. Bafetinib was created as an attempt for a more potent drug than imatinib, with efficacy against various point mutations in the Bcr-Abl kinase, with fewer adverse effects and with narrower kinase spectra, namely just Lyn and Bcr-Abl. In the search for a substance that fit the criteria mentioned, the crystal structure of imatinib bound to Abl was examined. This revealed a hydrophobic pocket around the phenyl ring adjacent to the piperazinylmethyl group of imatinib. Attempts to utilize this pocket to increase efficacy led to the addition of various hydrophobic groups including single fluoro, bromo and chloro substituents. Finally a trifluoromethyl group at position 3 was found to give the best results, with approximately 36-fold improvement over imatinib. The addition of a hydrophobic group now needed to be countered to sustain the solubility of the substance. Closer examination of the crystal structure of imatinib-kinase complex revealed Tyr-236 was in close proximity to the pyridine ring of imatinib, suggesting there was little or no room for a larger group there. With that in mind a more hydrophilic pyrimidine ring was substituted for the pyridine, which was found to increase solubility while leaving efficacy the same or even slightly greater. Finally to improve the hydrogen bonding of the piperazine ring of imatinib with Ile-360 and His-361, pyrrolidine and azetidine derivatives were introduced. The most promising substance from these final modifications was labeled NS-187.

The FDA granted NS-187 orphan drug status in 2007 for the treatment of chronic myeloid leukemia.