PD173955

PD173955 is a potent inhibitor of Bcr-Abl, Src and Yes with IC50 value of 1-2 nM, 300 nM and 175 nM, respectively [1-3].

Bcr-Abl is a protein tyrosine kinase which has oncogenic potential. Src is an enzyme and plays an important role in a variety of cancer cells survival, angiogenesis, proliferation and invasion pathways. Yes is a proto-oncogene tyrosine-protein kinase smf belongs to the Src kinase family [1-3].

PD173955 is a potent Bcr-Abl, Src and Yes inhibitor. When tested with CML CD34+ GM progenitors, PD173955 inhibited KL-dependent proliferation at an IC50 value of 50 nM and GM-CSF-dependent cell growth at an IC50 value of 1μM and the maximum inhibition was achieved at the dose of 25 nM. It was shown that PD173955 reduced the fractions of cells in G2-M phase and increased the cells in G1 phase with significant difference [2]. In HT29 cells, PD173955 treatment inhibited Src auot-phosphorylation in a dose dependent manner. Further, PD173955 showed inhibition on cell growth with IC50 value of 800 nM without morphologic changes and high concentrations arrested cell cycle at the M phase [1]. When tested with Bcr-Abl-depedent cell lines K562 and RWLeu4, PD173955 showed inhibition on cell proliferation with the IC50 value of 35 and 10 nM, respectively and arrested cell cycle in G1 phase at the low nanomolar [3].

References:
[1].  Windham, T.C., et al., Src activation regulates anoikis in human colon tumor cell lines. Oncogene, 2002. 21(51): p. 7797-807.
[2].  Strife, A., et al., Direct evidence that Bcr-Abl tyrosine kinase activity disrupts normal synergistic interactions between Kit ligand and cytokines in primary primitive progenitor cells. Mol Cancer Res, 2003. 1(3): p. 176-85.
[3].  Wisniewski, D., et al., Characterization of potent inhibitors of the Bcr-Abl and the c-kit receptor tyrosine kinases. Cancer Res, 2002. 62(15): p. 4244-55.

Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571).[Pubmed:12154025]

Cancer Res. 2002 Aug 1;62(15):4236-43.

The inadvertent fusion of the bcr gene with the abl gene results in a constitutively active tyrosine kinase (Bcr-Abl) that transforms cells and causes chronic myelogenous leukemia. Small molecule inhibitors of Bcr-Abl that bind to the kinase domain can be used to treat chronic myelogenous leukemia. We report crystal structures of the kinase domain of Abl in complex with two such inhibitors, imatinib (also known as STI-571 and Gleevec) and PD173955 (Parke-Davis). Both compounds bind to the canonical ATP-binding site of the kinase domain, but they do so in different ways. As shown previously in a crystal structure of Abl bound to a smaller variant of STI-571, STI-571 captures a specific inactive conformation of the activation loop of Abl in which the loop mimics bound peptide substrate. In contrast, PD173955 binds to a conformation of Abl in which the activation loop resembles that of an active kinase. The structure suggests that PD173955 would be insensitive to whether the conformation of the activation loop corresponds to active kinases or to that seen in the STI-571 complex. In vitro kinase assays confirm that this is the case and indicate that PD173955 is at least 10-fold more inhibitory than STI-571. The structures suggest that PD173955 achieves its greater potency over STI-571 by being able to target multiple forms of Abl (active or inactive), whereas STI-571 requires a specific inactive conformation of Abl.

PD173955 is src family-selective tyrosine kinase inhibitor with IC50 of ~22 nM for Src, Yes and Abl kinase; less potent for FGFRα and no activity on InsR and PKC.

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