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Cancer Res. 2009, 69:2384�?2. 8. Wolff NC, Veach DR, Tong WP, Bornmann WG, Clarkson B, Ilaria RL Jr. PD166326, a novel tyrosine kinase inhibitor, has greater antileukemic activity than imatinib mesylate in a murine model of chronic myeloid leukemia. Blood. 2005, 105:3995�?003. 9. Schenone S, Brullo C, Musumeci F, Botta M. Novel dual Src/Abl inhibitors Fostamatinib 1025687-58-4 for hematologic and solid malignancies. Expert Opin Investig Drugs. 2010, 19:931�?5. 10. Weisberg E, Choi HG, Ray A, et al. Discovery of a small-molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFRalpha, Kit, and Src kinases: novel type II inhibitor of gatekeeper mutants. Blood. 2010, 115:4206�?6. Woessner et al. Page 16 Cancer J. Author manuscript, available in PMC 2012 May 1.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Figure 1. p210 BCR-ABL functional domains and effects of downstream signaling BCR-ABL signaling leads to enhanced proliferation, reduced apoptotic potential, and altered cell adhesion. Contributions from both BCR and ABL domains on downstream signaling are illustrated. Dashed lines indicate additional intermediate signaling steps not detailed in this figure. CC, coiled-coil, S/T kinase, serine/theronine kinase, DH, Dbl homology, PH, Pleckstrin homology, SH2 or SH3, Src homology 2/3, Y kinase, tyrosine kinase, DBD, DNA binding domain, ABD, actin binding domain.. Woessner et al. Page 17 Cancer J. Author manuscript, available in PMC 2012 May 1.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Woessner et al. Page 18 Table 1 Drugs developed for CML therapy with activity against ABL-kinase and other kinases listed. NA, not active. Novel ABL Inhibitors Inhibitor Non-ABL Kinase Target T315I Status Reference DCC-2036 Src, Lyn, Fgr, Hck, Flt3, Tie-2 Active Phase I/II NCT00827138 GNF compounds ABL only Active Pre-clinical 1 ON012380 ABL only Active Pre-clinical 2 PPY-A ABL only Active Pre-clinical 3,4 SGX393 ABL only Active Pre-clinical 5 XL228 Aurora A/B, FAK, Src Active Phase I – terminated NCT00464113 MK-0457 Aurora A-C, Flt-3 Active Phase II – terminated NCT00405054 AT9283 Aurora A/B, JAK2/3 Active Phase I/II NCT00522990 danusertib Aurora A-C, Ret, Trk-A, FGFR-1 Active Phase II NCT00335868 ponatinib Flt3, FGFR, VEGFR, c-kit, PDGFR Active Phase II NCT01207440 bafetenib Lyn NA Phase I – development unlikely NCT00352677 AP23464 Src family Active Pre-clinical 6 bosutinib Src, TEC, STE20, CAMK2G NA Phase I/II/III NCT00811070, NCT00261846 DSA compounds Src Active Pre-clinical 7 PD166326 Src NA No trials or recent reports 8 saracatinib Src family NA Not in trials for CML 9 HG-7-85-01 Src, PDGFR, VEGFR, FLT3, Ret, Tie-2, Kit, DDR1, b-raf Active Pre-clinical 10 Cancer J.
Author manuscript, available in PMC 2012 May 1. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript W