Overcoming STI571 Resistance

While the kinase domain mutations that still retain some STI571 sensitivity (IC50<3 uM) may be overcome with more potent inhibitors that interact with the STI571 binding conformation, the resistance caused by mutants in the G-loop or the T315I mutant may require inhibitors that bind to Abl in an alternative mode or target the same conformation without engaging in an H-bond with the gatekeeper residue T315. Targeting the active, ATP-binding conformation of Abl has the advantage that the likelihood of emergence of resistant mutants is reduced. Prototype compounds in this regard are the pyrido[2,3-d]pyrimidine derivatives, one of which has been shown to bind to the catalytically active conformation of the Abl kinases, although the DFG motif is in a conformation that is unsuitable for optimal binding of ATP (Nagar et al. 2002). In addition, this pyrido[2,3-d]pyrimidine derivative has been reported to inhibit various mutants of the G-loop, the M351T mutant, as well as the A-loop mutant H396P, but not T315I (Dorsey et al. 2000; La Rosée et al. 2002; Cowan-Jacob et al. 2004). However, because the conformation of activated protein kinases is highly conserved, a major disadvantage of these types of inhibitors is the lack of selectivity against other kinases which might limit their tolerability (Kraker et al. 2000).

In contrast to the highly conserved conformations of activated protein kinases, the inactive states of protein kinases often adopt conformations in which there are large variations in size and shape of the ATP-binding pocket (Huse and Kuriyan 2002). Although targeting the inactive conformation of kinases may result in a better selectivity profile, the caveat is that these inhibitors will interact with many residues not involved in binding ATP, allowing mutations to arise which will prevent binding of the inhibitor without affecting the kinase activity.

Treatment strategies geared towards improving the STI571 therapy and/ or circumventing STI571 resistance are multiple and may include:

1. Inhibition of other kinases acting downstream of Bcr-Abl, such as the Src family members Lyn and Hck (Danhauser-Riedel et al. 1996; Donato et al. 2003; Warmuth et al. 2003) or Btk (Hofmann et al. 2002b)

2. Inhibitors targeting other signaling molecules like Mek/Erk (Yu et al. 2002), PI3 K (Klejman et al. 2002), farnesyltransferase inhibitors (Topaly et al. 2002; Daley 2003; Hoover et al. 2002), protein degradation (Gatto et al. 2001), or Hsp90 (Gorre et al. 2002), all of which have shown to enhance the antiproliferative effects of cells expressing STI571 resistant Bcr-Abl

The most likely treatment of malignancies targeted by STI571 will be a cocktail of drugs designed to inhibit a particular class of STI571-resistant mutations or a mechanism of resistance reminiscent to the treatment of

HIV. Similar treatment strategies are likely to be applied in diseases other than CML where the drug targets the PTK of c-Kit and PDGFR (i.e., CMML, GIST, HES).

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