SUPPLEMENTARY INFORMATION

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1 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 VEGFR um RET, TIE2 Approved 1 Bosutinib (SKI- 606, PF ) Breast carcinoma, glioblastoma, Ph+ CML SRC, ABL Approved 2,3 340 Crizotinib (PF ) NSCLC MET ALK, Approved 3,4 Vandetinib Thyroid, NSCLC VEGFR2, VEGFR3, EGFR RET Approved 3 Sunitinib RCC, GIST PDGF, VEGF RET, Approved 3,5 Lestaurtinib (CEP- 701) AML, ALL JAK2, TRKB, TRKC Phase III 3 Neratinib Breast cancer HER K d > 3000 Phase III 3 AT9283 Multiple myeloma, AURKA, IC50 < Phase II 6

2 leukaemia JAK 10 R406 Rheumatoid arthritis, lymphoma SYK Phase II 3 Foretinib (GSK , XL880) Triple negative metastatic breast cancer, HER2 + breast cancer, NSCLC VEGFR PDGFRβ, TIE2, Phase Ib/II 3,7 MK MET 24 VEGFR Phase I/II 8 BMS / ASLAN002 MET Phase I 9 LY Advanced cancers MET Phase I 10 SU VEGFR KIT Phase I 3 S49076 FGFR 7 2 Phase I 11 BMS MET ** ** ** VEGFR2, Phase I 12 BGB324 (R428) Breast cancer, RET IC50* > 1400 VEGFR, ABL, TIE2 Phase I 3 Amuvatinib (MP- 470) Neuroendocrine, lung, and 1 um Developm ent 13

3 endometrial cancers RET, RAD51, discontin ued JNJ Solid, AML M- CSFR, K d > 3000 LCK Preclinical 3,14 GSK Solid PERK Preclinical 15 Ki Breast cancer, autoimmune disorders M- CSFR KIT Preclinical 3 6g, MERTK, MET TYRO3 Preclinical 16 Diaminopyrim idine Pancreatic cancer 27 IC50 < 200 IC50 < 200 AURKA, AURKB Preclinical Compound 52 MERTK 11.3 um Spiroindoline TYRO3 480 Preclinical 17 Preclinical 18,19 UNC569 ALL MERTK MAPKA PK2, RET Preclinical 20,21 UNC1062 Metastatic melanoma MERTK Preclinical 22, UNC1666 AML MERTK, Preclinical 24***

4 UNC2025 ALL, AML MERTK, TRKC Preclinical 25***, 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, (2011). 2. Zhang, Y.X., et al. is a potential target for therapeutic intervention in breast cancer progression. Cancer research 68, (2008). 3. Davis, M.I., et al. Comprehensive analysis of kinase inhibitor selectivity. Nature biotechnology 29, (2011). 4. Mollard, A., et al. Design, Synthesis and Biological Evaluation of a Series of Novel Axl Kinase Inhibitors. ACS medicinal chemistry letters 2, (2011). 5. Kumar, R., et al. Myelosuppression and kinase selectivity of multikinase angiogenesis inhibitors. Br J Cancer 101, (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, (2009). 7. Liu, L., et al. Novel mechanism of lapatinib resistance in HER2- positive breast tumor cells: activation of. Cancer research 69, (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, (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 ), a selective and orally efficacious inhibitor of the Met kinase superfamily. Journal of medicinal chemistry 52, (2009). 10. Yan, S.B., et al. LY 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, (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, (2013). 12. Peters, S. & Adjei, A.A. MET: a promising anticancer therapeutic target. Nature reviews. Clinical oncology 9, (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 , 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, (2009).

5 15. Axten, J.M., et al. Discovery of 7- methyl- 5- (1- {[3- (trifluoromethyl)phenyl]acetyl}- 2,3- dihydro- 1H- indol- 5- yl)- 7H- p yrrolo[2,3- d]pyrimidin- 4- amine (GSK ), a potent and selective first- in- class inhibitor of protein kinase R (PKR)- like endoplasmic reticulum kinase (PERK). Journal of medicinal chemistry 55, (2012). 16. Suarez, R.M., et al. Inhibitors of the TAM subfamily of tyrosine kinases: synthesis and biological evaluation. European journal of medicinal chemistry 61, 2-25 (2013). 17. Huang, X., et al. Structural insights into the inhibited states of the Mer receptor tyrosine kinase. Journal of structural biology 165, (2009). 18. Powell, N.A., et al. Novel and selective spiroindoline- based inhibitors of Sky kinase. Bioorganic & medicinal chemistry letters 22, (2012). 19. Powell, N.A., et al. Optimization of highly selective 2,4- diaminopyrimidine- 5- carboxamide inhibitors of Sky kinase. Bioorganic & medicinal chemistry letters 23, (2013). 20. Liu, J., et al. Discovery of Novel Small Molecule Mer Kinase Inhibitors for the Treatment of Pediatric Acute Lymphoblastic Leukemia. ACS medicinal chemistry letters 3, (2012). 21. Christoph, S., et al. UNC569, a novel small- molecule mer inhibitor with efficacy against acute lymphoblastic leukemia in vitro and in vivo. Molecular cancer therapeutics 12, (2013). 22. Schlegel, J., et al. MERTK receptor tyrosine kinase is a therapeutic target in melanoma. J Clin Invest 123, (2013). 23. Liu, J., et al. UNC1062, a new and potent Mer inhibitor. European journal of medicinal chemistry 65, (2013). 24. Lee- Sherick, A.B., et al. UNC16666, a dual Mer and Flt- 3 tyrosine kinase small molecule inhibitor in acute myeloid leukemia. Blood 122, 3849 (2013). 25. DeRyckere, D., et al. Development of a novel small molecule MER tyrosine kinase inhibitor with therapeutic in cell culture and mouse models of acute lymphoblastic leukemia. American Association of Cancer Researchers Annual Meeting, San Diego, CA, Abstract #1740 (2014). 26. Zhang, W., et al. UNC2025, a potent and orally bioavailable MER/ dual inhibitor. Journal of medicinal chemistry 57, (2014). 27. Paolino, M., et al. The E3 ligase Cbl- b and TAM receptors regulate cancer metastasis via natural killer cells. Nature 507, (2014).