1. Chronic myelogenous leukemia Uncommon disease Highly lethal when ineffectively Rxd Most pts are in their 50s+60s The molecular understanding of this disease is remarkably high. It has offered an opportunity to deliver superb treatment That makes good biological, biochemical, genetic, and clinical sense But there are also problems.

4. Normal bone marrow

5. Bone Marrow sample of a CML patient. Marked expansion of myelocytic cells

8. The Philadelphia Chromosome= a distinct+reciprocal 9 22 translocation

11. (years)

12. Abl=tyr kinase Imatinib=Gleevec

14. Abl=tyr kinase ATP binding/catalytic domain

17. Imatinib prolongs life in chronic phase CML

18. Natural History of Imatinib-Resistant CML development Blood Count Cells x 10 3 5 10 15 years 1 2 Resistance

20. Abl=tyr kinase

23. Figure 4. BCR-ABL1E255V/T315I Exhibits Severely Compromised TKI Binding and Is Detected at Clinical Relapse on Ponatinib(A) Summary of BCR-ABL1 cloning and sequencing for patient #38 (Ph+ ALL) at baseline (upper) and EOT (lower) by cloning and sequencing indiv... Zabriskie et al, BCR-ABL1 Compound Mutations Combining Key Kinase Domain Positions Confer Clinical Resistance to Ponatinib in Ph Chromosome-Positive Leukemia, Cancer Cell Volume 26, Issue 3, 2014, 428–442 http://dx.doi.org/10.1016/j.ccr.2014.07.006

26. JM Zhang et al. Nature 463,28 2010 NMR spectroscopy provides evidence for GNF-2 binding to the C-terminal myristate pocket of Abl.

27. JM Zhang et al. Nature 000, 1-6 (2010) doi:10.1038/nature08675 Location and cellular IC 50 of Bcr–Abl GNF-2 resistance mutations. JM Zhang et al. Nature 463,28 2010

29. JM Zhang et al. Nature 000, 1-6 (2010) doi:10.1038/nature08675 In vivo efficacy studies with GNF-5 on wild-type and T315I Bcr–Abl dependent proliferation in xenograft and bone-marrow transplantation models. JM Zhang et al. Nature 463,28 2010

30. JM Zhang et al. Nature 000, 1-6 (2010) doi:10.1038/nature08675 Location and cellular IC 50 of Bcr–Abl GNF-2 resistance mutations. JM Zhang et al. Nature 463,28 2010

31. Bhang et al, Nature Medicine, 2014

32. Bar-coded clones conferring resistance to an allosteric bcr-abl inhibitor Bhang et al, Nature Medicine, 2014