Slide 1: Discovery and characterization of IRAKIMiDs: degraders targeting IRAK4 and IMiD substrates
Discovery and characterization of IRAKIMiDs: degraders targeting both IRAK4 and IMiD substrates for oncology indications. Matthew Weiss Northeastern Section, ACS (NESACS)
Slide 2: Forward-Looking Statements
Forward-Looking Statements This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 (PSLRA) and other federal securities laws. These statements include information about our current and future prospects and our operations and fi
Slide 3: Biology of Targeted Protein Degradation (TPD)
Biology of Targeted Protein Degradation (TPD) Target Protein 1 Hetero- 2 bifunctional Degrader Targeted Protein Degradation E3 Ubiquitin Ubiquitin Chain E2 • ONLY binding site required • Ternary complex-based selectivity • Sub-stoichiometric, catalytic 3 • Protein re-synthesis rate Amino Acids from
Slide 4: Building a Franchise Around IRAK4 Degradation
Building a Franchise Around IRAK4 Degradation Clinical and Genetic Validation for Oncologic and Inflammatory Conditions IL-1aβ IL-18 IL-33 IL-36 TLRs (TLR 4,7,8,9) IL1-Ra /IL-1b: Rheumatologic Diseases IL-1R M YD88 Mutations: Heme Onc MyD88 MyD88 IL-1β: CANTOS Data IRAK4 IRAK1 IRAK2 TRAF6 IL-36: Gen
Slide 5: Building a Franchise Around IRAK4 Degradation: KT-474 and KT-413
Building a Franchise Around IRAK4 Degradation: Heterobifunctional Degraders KT-474 and KT-413 Pathway Program Indication(s) Discovery Preclinical Phase 1 Phases 2/3 Next Milestone Rights Patients Atopic Dermatitis, KT-474 Data 4Q22 Hidradenitis Suppurativa, IRAK4 Rheumatoid Arthritis, others IL-1R/T
Slide 6: Degradation of IRAK4: Modulating Proinflammatory Cytokines and Cellular Proliferation
Degradation of IRAK4: Modulating Proinflammatory Cytokines and Cellular Proliferation * Frequently mutated proteins in ABC-DLBCL • IRAK4 is a key component of the myddosome and its function is dependent on both its kinase activity and on its scaffolding properties • Activation of downstream pathways
Slide 7: Degradation of IRAK4 and IMiD Substrates in MYD88 MT DLBCL
Degradation of IRAK4 and IMiD Substrates: Targeting Redundant Pro-survival Pathways in MYD88MT DLBCL * Frequently mutated proteins in ABC-DLBCL • MYD88 L265P is a gain-of-function driver mutation which results in constitutive activation of the anti-apoptotic NFkB signaling pathway • Single-agent the
Slide 8: IRAKIMiD: Heterobifunctional Degrader & Molecular Glue
IRAKIMiD: Functioning as a Heterobifunctional Degrader & a Molecular Glue Heterobifunctional Degrader IRAK4 Degradation of IRAK4 CRBN IRAK4 CRBN ligand ligand Molecular Glue Ikaros Degradation of IMiD substrates (i.e., Ikaros and Aiolos) CRBN ©2022 KY MERA T HERAP EUT ICS, INC. P AGE 8
Slide 9: Differential Biology of Selective IRAK4 Degraders and IRAKIMiDs
Differential Biology of Selective IRAK4 Degraders and IRAKIMiDs • OCI-Ly10: DLBCL line expresses most prevalent mutation found in MYD88 (L265P) OCI-Ly10 CTG • Selective IRAK4 degrader (e.g., KTX-545) exhibits no anti-proliferative effect on OCI-Ly10 cells • Dual degrader of IRAK4 and IMiD substrates
Slide 10: Differential Biology of Selective IRAK4 Degraders and IRAKIMiDs
Differential Biology of Selective IRAK4 Degraders and IRAKIMiDs KTX-545 tested at 5 nM in OCI-Ly10 cells KTX-545 KT-413 Selective IRAK4 IRAKIMiD Degrader Degrader IRAK4 DC50 (nM) 1 6 Ikaros DC50 (nM) >1,000 2 Aiolos DC50 (nM) >1,000 2 KT-413 tested at 41 nM in OCI-Ly10 cells • Selective IRAK4 degrad
Slide 11: Identification and Optimization of IRAKIMiDs: Multi-Parameter Optimization
Identification and Optimization of IRAKIMiDs: Multi-Parameter Optimization • Challenges associated with IRAKIMiDs: • Independent SAR for the degradation of IRAK4 and IMiD substrates • Optimization of the physicochemical properties and pharmacokinetics in space beyond the rule of 5 (bRo5) • Developin
Slide 12: Identifying Scaffolds and Vectors for Linker Attachment
Identifying Scaffolds and Vectors for Linker Attachment: IRAK4 Degradation Achieved with Multiple Scaffolds and Vectors Subset of IRAK4 Ligands Capable of Inducing Degradation of IRAK4 Hinge binder Exit vector 1 Hinge Demonstrated the ability to induce degradation of Exit vector 2 IRAK4 using multip
Slide 13: Improving Degradation Efficiency and Selectivity
Improving Degradation Efficiency and Selectivity • Incorporation of a functional handles to control the directionality of the vector from POI can significantly increase the efficiency of POI degradation KTX-881 CRBN Ligand Linker KTX-353 KTX-671 KTX-315 KTX-881 KTX-353 Linker IRAK4 DC50 (nM) 23 6 IR
Slide 14: Optimizing IRAKIMiDs: Representative Motifs Explored
Optimizing IRAKIMiDs: Representative Motifs Explored • Extensive exploration of the IRAK ligand and linker required to accommodate SAR associated with both IRAK and IMiD degradation • Indazole scaffold chosen due to kinome selectivity, modularity and ability to easily modulate properties Cereblon Co
Slide 15: Embracing the Linker: Modulating Potency, Selectivity and Physicochemical Properties
Embracing the Linker: Modulating Potency, Selectivity and Physicochemical Properties • Linker can serve as a handle to modulate every aspect of a heterobifunctional degrader • Some of the lessons we have learned around linker design • Potency and Selectivity • Linker modulation can significantly imp
Slide 16: Building and Leveraging a Ternary Complex Model
Building and Leveraging a Ternary Complex Model: Enabling a Rational Degrader Design Strategy POM KTX-733 Co-crystal POM (CRBN-DDB1) Co-crystal KTX-733 and IRAK4 Early SAR informs design of ternary Ternary complex model to enable complex model rationale linker design ©2022 KY MERA T HERAP EUT ICS, I
Slide 17: Affinity of Ligands Doesn't Always Correlate with Degradation Efficiency
Affinity of Ligands Doesn’t Always Correlate with Degradation Efficiency IRAK Linker Ligand Degrader using novel CRBN ligand that doesn’t engage IMiDs Cereblon Binding IC50 (mM) KTX-326 KTX-951 KTX-178 IRAK Ligand Ligand A Ligand B Ligand C IRAK4 Kd (nM) 0.3 3.5 28 IRAK4 DC50 (nM) 8 18 15 • IRAK4 de
Slide 18: Modulating Potency and Intrinsic Stability
Modulating Potency and Intrinsic Stability trans isomer~10x more potent than cis for degradation of both IRAK4 and Ikaros KTX-435 KTX-582 KTX-955 IRAK4 DC50 (nM) 18 4 5 Ikaros DC50 (nM) 12 5 130 OCI-Ly10 CTG IC50 (nM) 270 28 1,800 HLM (mL/min/mg) 60 48 4 Linker modifications could enable an improvem
Slide 19: Merging Intrinsic Stability with IMiD Activity: Impact on Oral Absorption
Merging Intrinsic Stability with IMiD Activity: Impact on Oral Absorption linker design to retain IMiD activity while improving HLM KTX-955 KTX-497 KTX-612 IRAK4 DC50 (nM) 5 3 7 Ikaros DC50 (nM) 130 25 6 HLM (mL/min/mg) 4 1 3 RLM (mL/min/mg) 4 3 2 ©2022 KY MERA T HERAP EUT ICS, INC. P AGE 19
Slide 20: Merging Intrinsic Stability with IMiD Activity: Impact on Oral Absorption
Merging Intrinsic Stability with IMiD Activity: Impact on Oral Absorption linker design to retain IMiD activity while improving HLM KTX-955 KTX-497 KTX-612 IRAK4 DC50 (nM) 5 3 7 Ikaros DC50 (nM) 130 25 6 HLM (mL/min/mg) 4 1 3 RLM (mL/min/mg) 4 3 2 Rat PPB (Fu) 0.096 0.079 0.026 Rat IV CL (mL/min/kg)
Slide 21: Balancing Metabolic Stability and Potency
Balancing Metabolic Stability and Potency R= R= KTX-582 KTX-961 • Methoxy analogs consistently more IRAK4 DC50 (nM) 4 19 metabolically stable than their tertiary Ikaros DC50 (nM) 5 28 alcohol counterparts HLM (mL/min/mg) 48 4 • Tertiary alcohols consistently MDCK Passive Perm. (x10-6 cm/s) 4.9 2.1 d
Slide 22: Potency and Pharmacokinetics: Reducing H-Bond Donors to Improve Oral Absorption
Potency and Pharmacokinetics Reducing H-Bond Donors to Improve Oral Absorption KTX-612 KTX-951 IRAK4 DC50 (nM) 7 13 Ikaros DC50 (nM) 6 14 Aiolos DC50 (nM) 4 13 OCI-Ly10 CTG IC50 (nM) 10 35 HLM (mL/min/mg) 3 2 RLM (mL/min/mg) 2 3 Rat PPB (Fu) 0.026 0.073 Rat IV CL (mL/min/kg) 14 4.0 Rat PO PK (10 mg/
Slide 23: KTX-951: Favorable Pharmacokinetics Across Species
KTX-951: Favorable Pharmacokinetics Across Species Human Rat Dog PPB (Fu) 0.12 0.073 0.072 KTX-951 IV CL (mL/min/kg) -- 4.0 4.4 PO %F (10 mg/kg) -- 22 57 MDCK Passive Permeability (x10-6 cm/s) 1.1 FaSSIF solubility (mM) 21 FeSSIF solubility (mM) 20 ©2022 KY MERA T HERAP EUT ICS, INC. P AGE 23
Slide 24: KT-413 is Highly Active on Intermittent Dosing Regimens
KT-413 is Highly Active on Intermittent Dosing Regimens • In the OCI-Ly10 MYD88MT xenograft model, intermittent dosing of KT-413 induced strong antitumor activity, including complete or partial regressions • Minimally active dose of 3 mg/kg D1,2 showed extended tumor exposure and strong degradation
Slide 25: KT-413 Shows Regressions in MYD88 MT PDX Models
KT-413 Shows Regressions in MYD88MT Patient-Derived Xenograft (PDX) Models KT-413 PDX Ly14019CD79MT/MYD88MT Model MYD88 CD79B TNFAIP3 Other (%TGI) LY14019 L265P MT MT 100 LY2264 L265P MT IRF4 100 LY2298 L265P MT BCL2/BCL6 90 LY12699 L265P MT 87 LY2345 WT MT 70 LY2301 WT 30 LY0257 L265P BCL2/BCL6/IKZ
Slide 26: Building an IRAK4 Franchise: Delivering on the Promise of Targeted Protein Degraders
Building an IRAK4 Franchise: Delivering on the Promise of Targeted Protein Degraders • Selective IRAK4 degrader KT-474 • First proof-of-mechanism for TPD in a randomized, placebo-controlled healthy volunteer study • IRAKIMiD KT-413 • Potent degrader of IRAK4 and IMiD substrates • PK/PD shows sustain
Slide 27: Acknowledgments
Acknowledgments ©2022 KY MERA T HERAP EUT ICS, INC. P AGE 27