Supplementary Information S3 TAM- family small molecule kinase inhibitors in development Compound Indication(s) Target Profile Develop Primary Target MERTK TYRO3 Other targets ment Phase Refs Cabozantinib Thyroid, prostate, kidney, ovarian, lung, breast VEGFR2 7 42 um RET, TIE2 Approved 1 Bosutinib (SKI- 606, PF- 5208763) Breast carcinoma, glioblastoma, Ph+ CML SRC, ABL 52 0.6 110 61 Approved 2,3 340 Crizotinib (PF- 2341066) NSCLC MET 7.8 300 3.6 800 ALK, Approved 3,4 Vandetinib Thyroid, NSCLC VEGFR2, VEGFR3, EGFR 250 1400 93 RET Approved 3 Sunitinib RCC, GIST PDGF, VEGF 9 259 26 12 49 251 RET, Approved 3,5 Lestaurtinib (CEP- 701) AML, ALL 35 32 650 JAK2, TRKB, TRKC Phase III 3 Neratinib Breast cancer HER2 190 400 K d > 3000 Phase III 3 AT9283 Multiple myeloma, AURKA, IC50 < Phase II 6
leukaemia JAK 10 R406 Rheumatoid arthritis, lymphoma SYK 82 170 1900 Phase II 3 Foretinib (GSK1363089, XL880) Triple negative metastatic breast cancer, HER2 + breast cancer, NSCLC VEGFR2 0.1 11 0.3 2 PDGFRβ, TIE2, Phase Ib/II 3,7 MK- 2461 MET 24 VEGFR Phase I/II 8 BMS- 777607/ ASLAN002 MET 1.1 14 4.3 Phase I 9 LY2801653 Advanced cancers MET 11 2 0.8 1200 Phase I 10 SU- 14813 VEGFR 84 66 2400 KIT Phase I 3 S49076 FGFR 7 2 Phase I 11 BMS- 796302 MET ** ** ** VEGFR2, Phase I 12 BGB324 (R428) Breast cancer, RET 14 14 220 700 200 IC50* > 1400 VEGFR, ABL, TIE2 Phase I 3 Amuvatinib (MP- 470) Neuroendocrine, lung, and 1 um Developm ent 13
endometrial cancers RET, RAD51, discontin ued JNJ- 28312141 Solid, AML M- CSFR, 5.3 12 86 K d > 3000 LCK Preclinical 3,14 GSK2606414 Solid PERK 2700 470 Preclinical 15 Ki- 20227 Breast cancer, autoimmune disorders M- CSFR 140 460 2000 KIT Preclinical 3 6g, MERTK, MET 39 42 200 TYRO3 Preclinical 16 Diaminopyrim idine Pancreatic cancer 27 IC50 < 200 IC50 < 200 AURKA, AURKB Preclinical 4 220 Compound 52 MERTK 11.3 um Spiroindoline TYRO3 480 Preclinical 17 Preclinical 18,19 UNC569 ALL MERTK 37 2.9 141 48 MAPKA PK2, RET Preclinical 20,21 UNC1062 Metastatic melanoma MERTK 85 1.1 60 Preclinical 22,23 6.4 UNC1666 AML MERTK, 30 0.4 39 Preclinical 24***
UNC2025 ALL, AML MERTK, 7.5 0.7 18 TRKC Preclinical 25***, 26 2.6 LDC1267 Metastatic melanoma MERTK,, TYRO3 29 IC50 < 5 8 LCK Preclinical 27 *Indicates in cell- based kinase assays. All other values represent in biochemical assays. ** Inhibitory reported but no quantitative information available. *** Meeting abstract AML, acute myeloid leukaemia; ALK, anaplastic lymphoma kinase; ALL, acute lymphoid leukaemia; AURK, aurora kinase; CML, chronic myeloid leukaemia; EGFR, epidermal growth factor receptor; Fms- like tyrosine kinase 3; GIST, gastric stromal intestinal tumour; IC50, half- maximal inhibitory concentration; JAK, Janus kinase; K d, dissociation constant; MAPKAPK2, MAPK- activated protein kinase 2; M- CSFR, macrophage colony- stimulating factor receptor; NSCLC, non- small- cell lung cancer; PDGF, platelet- derived growth factor; PERK, PRKR- like endoplasmic reticulum kinase; Ph, Philadelphia chromosome; RCC, renal cell carcinoma; SYK, spleen tyrosine kinase; TRK, tropomyosin- related kinase; VEGFR, vascular endothelial growth factor receptor. 1. Yakes, F.M., et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Molecular cancer therapeutics 10, 2298-2308 (2011). 2. Zhang, Y.X., et al. is a potential target for therapeutic intervention in breast cancer progression. Cancer research 68, 1905-1915 (2008). 3. Davis, M.I., et al. Comprehensive analysis of kinase inhibitor selectivity. Nature biotechnology 29, 1046-1051 (2011). 4. Mollard, A., et al. Design, Synthesis and Biological Evaluation of a Series of Novel Axl Kinase Inhibitors. ACS medicinal chemistry letters 2, 907-912 (2011). 5. Kumar, R., et al. Myelosuppression and kinase selectivity of multikinase angiogenesis inhibitors. Br J Cancer 101, 1717-1723 (2009). 6. Howard, S., et al. Fragment- based discovery of the pyrazol- 4- yl urea (AT9283), a multitargeted kinase inhibitor with potent aurora kinase. Journal of medicinal chemistry 52, 379-388 (2009). 7. Liu, L., et al. Novel mechanism of lapatinib resistance in HER2- positive breast tumor cells: activation of. Cancer research 69, 6871-6878 (2009). 8. Katz, J.D., et al. Discovery of a 5H- benzo[4,5]cyclohepta[1,2- b]pyridin- 5- one (MK- 2461) inhibitor of c- Met kinase for the treatment of cancer. Journal of medicinal chemistry 54, 4092-4108 (2011). 9. Schroeder, G.M., et al. Discovery of N- (4- (2- amino- 3- chloropyridin- 4- yloxy)- 3- fluorophenyl)- 4- ethoxy- 1- (4- fluorophenyl )- 2- oxo- 1,2- dihydropyridine- 3- carboxamide (BMS- 777607), a selective and orally efficacious inhibitor of the Met kinase superfamily. Journal of medicinal chemistry 52, 1251-1254 (2009). 10. Yan, S.B., et al. LY2801653 is an orally bioavailable multi- kinase inhibitor with potent against MST1R, and other oncoproteins, and displays anti- tumor activities in mouse xenograft models. Investigational new drugs 31, 833-844 (2013). 11. Burbridge, M.F., et al. S49076 is a novel kinase inhibitor of, and FGFR with strong preclinical alone and in association with bevacizumab. Molecular cancer therapeutics 12, 1749-1762 (2013). 12. Peters, S. & Adjei, A.A. MET: a promising anticancer therapeutic target. Nature reviews. Clinical oncology 9, 314-326 (2012). 13. Qi, W., et al. MP470, a novel receptor tyrosine kinase inhibitor, in combination with Erlotinib inhibits the HER family/pi3k/akt pathway and tumor growth in prostate cancer. BMC cancer 9, 142 (2009). 14. Manthey, C.L., et al. JNJ- 28312141, a novel orally active colony- stimulating factor- 1 receptor/fms- related receptor tyrosine kinase- 3 receptor tyrosine kinase inhibitor with potential utility in solid, bone metastases, and acute myeloid leukemia. Molecular cancer therapeutics 8, 3151-3161 (2009).
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