SEEDSUPPLY for Drug Discovery Supply hit compounds and target proteins

September, 2017 SEEDSUPPLY Inc. CEO Naoki Tarui

SEEDSUPPLY Inc. Company Overview

Established: May 15, 2017 (Spin-out from Takeda Pharmaceutical Company)

Location: Japan (Fujisawa, Kanagawa)

Business: ∙ Support for drug discovery ∙ in-house drug discovery (Joint projects with pharma/academia)

Customers: From big pharma to small biotech, worldwide

Key expertise: ∙ Finding of binding compounds to a target ∙ Identification of binding proteins to a compound (by using a unique binder selection technology)

Ownership: privately owned, TAKEDA<20%

Employees: 5

1 SEEDSUPPLY Inc. New solution for drug discovery

1993 HTS start high throughput/miniaturization

Biochemical assay Reduction of tractable targets

Increase of targets that cannot be Target deconvolution handled by conventional HTS (Identification of proteins that bind to compounds from our Conventional HTS Our HTS protein library without labeling compounds/proteins) Target applicable Target Every target to HTS Assay Each method for One method method each target Detection Various detectors LCMS

2 Binder selection technology

Binder selection technology Hit binder finding Target • + Soluble protein • GPCR Membrane fraction • compounds Target Ion channel Microsomes • Transporter Organelle • Transcription Unique chromatography DNA/RNA factor technology × (high throughput/ Takeda library compounds miniaturization) (400K) • High capacity • Low cost LC/MS Binder Hit binder 50 Inhibitor 40 Activator 30 Agonist 20 Antagonist Non-binders 10 Modulator Stabilizer

MS signal intensity 0 0 1 Time (min)

3 SEEDSUPPLY Inc. Profile of library

Out of Number of compounds: 400K RO5  Drug-like/lead-like compounds  LC/MS-parameters confirmed RO3.5  Soluble at 30 uM in buffer 31%  Cell-growth inhibition tested RO5  No reactive compounds 60%

Molecular Weight logP QED Ave. 374.7 Ave. 2.60 Ave. 0.70

15% 15% 15%

10% 10% 10%

5% 5% 5% % of compounds of % compounds of % compounds of % 0% 0% 0% 2 1 0 1 2 3 4 5 6 7 8 9 - - 10 100 150 200 250 300 350 400 450 500 550 600 .05 .15 .25 .35 .45 .55 .65 .75 .85 .95 ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ Molecular weight AlogP by PipelinePilot QED by PipelinePilot

4 SEEDSUPPLY Inc. Hit binder finding

Biochemical vs. binding Fkinase inhibitor AA transporter Hit binder Binding Kd (nM) IC50 7.5 SS-409 241 4.6E-06

7.0 SS-731 18 3.1E-09 Silent binder SS-869 25 1.7E-09 6.5 SS-968 51 1.3E-08 SS-438 18 1.9E-09 6.0 SS-013 21 2.7E-09 SS-713 28 4.6E-09 5.5 NR agonist 5.0 Hit binder Binding Kd (nM) EC50 4.5 SS-931 33 7.1E-09 4.5 5 5.5 6 6.5 7 7.5 SS-994 34 2.2E-08 SS-798 99 1.0E-08 AA uptake assay (pIC50) SS-703 453 6.9E-08 SS-285 88 4.6E-09 SS-134 20 2.9E-08 SS-539 37 3.4E-07

5 SEEDSUPPLY Inc. Target deconvolution (Binding protein finding )

Human cDNA clone library Membrane protein Soluble protein in vitro translation Compound A with wheat germ extract NH 3 Mammalian cell expression

Human proteins Protein library 18,000 proteins (one protein/well)

(Pilot study)

Binder selection technology 1: FKBP1A Binder 2: FKBP2

Non- 11 3: FKBP5 binder 4: FKBP3 label-free Target compounds 5: FKBP4 FK506 4 5 S 4 5

MS MS signal of FK506 6 22 6 Advantages: 33 • No label FK506 of signal MS (diclofena standard internal / Binding protein • Membrane proteins ProteinProtein No.No. • Low-expressed proteins

6 SEEDSUPPLY Inc. 7 SEEDSUPPLY Inc.