Replies to post #113916 on Biotech Values

[biomaven0]

Pfizer's (PFE.N) bosutinib, which is currently in late stage trials for CML, is also known to block SRC, as is Ariad's (ARIA.O) ponatinib, which is undergoing mid-stage testing.

The difference is that bosutinib is more of a dual SRC-Abl inhibitor, whereas ponatinib is more of a specific Abl inhibitor that also hits SRC.

Here are the IC50's (subject to the usual disclaimers that this preclinical numbers might not translate into the real world):

Bosutinib: 1.4 nM vs. c-Abl (wild type); 3.8 vs. SRC
Ponatinib: 0.37 nM vs c-Abl (wild type); 5.4 vs SRC

Now 5.4 nM might be within reach for Ponatinib (it easily hits T315I which has an IC50 of 2.0), but it's maybe a stretch. On the other hand, Ponatinib is very potent against LYN (IC50 of 0.24), which is a member of the SRC family and might actually be the crucial bad actor here.

For example, LYN in gliablastoma:

Lyn Kinase Activity Is the Predominant Cellular Src Kinase Activity in Glioblastoma Tumor Cells

1. Michelle R. Stettner1,
...
8. Candece L. Gladson1,4

Abstract

Cellular Src activity modulates cell migration, proliferation, and differentiation, and recent reports suggest that individual members of the Src family may play specific roles in these processes. As we have found that Lyn, but not Fyn, activity promotes migration of glioblastoma cells in response to the cooperative signal generated by platelet-derived growth factor receptor ß and integrin avß3, we compared the activity and expression of Lyn and Fyn in glioblastoma (grade IV) tumor biopsy samples with that in anaplastic astrocytoma (grade III) tumors, nonneoplastic brain, and normal autopsy brain samples. Lyn kinase activity was significantly elevated in glioblastoma tumor samples. Notably, the Lyn kinase activity accounted for >90% of pan-Src kinase activity in glioblastoma samples but only ˜30% of pan-Src kinase activity in the other groups. The levels of phosphorylation of the autophosphorylation site were consistent with significantly higher Lyn activity in glioblastoma tumor tissue than nonneoplastic brain. Although the normalized levels of Lyn protein and the relative levels of Lyn message were significantly higher in glioblastoma samples than nonneoplastic brain, the normalized levels of Lyn protein did not correlate with Lyn activity in the glioblastoma samples. There was no significant difference in the normalized levels of c-Src and Fyn protein and message in the glioblastoma and nonneoplastic brain. Immunostaining revealed that Lyn is located primarily in the glioblastoma cells in the tumor biopsies. These data indicate that Lyn kinase activity is significantly elevated in glioblastoma tumors and suggest that it is the Lyn activity that promotes the malignant phenotype in these tumors.