SMART Drugs Engineering Nature’s Solution to the Undruggable Target Challenge

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Cyclophilins: A Parallel Universe CYPA/Cyclosporine/Calcineurin CYPA interface Cyclosporine interface WARP DRIVE BIO, INC. 14
Key Characteristics of SMART: “Nature’s Modality” • Combines advantages of small molecules (cell penetrant) and protein therapeutics (able to engage flat surfaces) to bind ‘undruggable’ targets • The modality is clinically validated: Three approved drugs exploit the binding modality (Rapamycin, FK506, Cyclosporine) • Follows rules of naturally occurring protein-protein interactions o binding to functional hydrophobic hotspots o cooperative binding mode, achieving high affinity and selectivity • Exploits inherent adaptability of presenter protein binding surface • Target selectivity of the modality is reprogrammable by modifying the variable region of the small molecule Warp Drive is Engineering this Modality to Develop SMART Drugs with these Attributes WARP DRIVE BIO, INC. 15
Page 1 and 2: SMART Drugs: Engineering Nature’s
Page 3 and 4: The Problem of Intractable Targets
Page 5 and 6: How Does Nature Achieve the ‘Impo
Page 7 and 8: Cooperative Binding Mimics Natural
Page 9 and 10: Nature Can Reprogram Target Selecti
Page 11 and 12: Surface of FKBP12 Adapts Itself to
Page 13: Prolyl Isomerases (e.g., FKBP12) Ar
Page 17 and 18: Two Presenters, Two Paths for SMART
Page 19 and 20: Two-Pronged Proprietary Discovery P
Page 21 and 22: Primary Screening Assay: TR-FRET Ex
Page 23 and 24: Large-Scale Library Approach (10^6)
Page 25 and 26: Synthetic Crystallography: Concept
Page 27 and 28: Solving the Structure of KRAS-FKBP
Page 29 and 30: FKBP Competes for RAS Effector Bind
Page 31: Summary • Nature has evolved a ge

SMART Drugs Engineering Nature’s Solution to the Undruggable Target Challenge

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