Kymera Therapeutics, Inc. · NASDAQ:KYMR
Kymera Therapeutics — Technical Presentation (May 2022)
12 slides from Kymera Therapeutics's technical presentation, May 2022
Slide 1: STAT3 degraders inhibit Th17 development and cytokine production in murine arthritis
STAT3 degraders inhibit Th17 development and cytokine production resulting in profound inhibition of collagen-induced autoimmune murine arthritis Cedric Hubeau, Jeffrey Sullivan, Crystal Brown, Michele Mayo, Vaishali Dixit, Bradley Enerson, Haojing Rong, Bin Yang, Chris De Savi, Jared Gollob, Nello
Slide 2: Disclosures
DISCLOSURES Jeffrey Sullivan, Crystal Brown, Michele Mayo, Vaishali Dixit, Bradley Enerson, Haojing Rong, Bin Yang, Chris De Savi, Jared Gollob, Nello Mainolfi, Anthony Slavin are Kymera Therapeutics employees and equity owners. Cedric Hubeau is a former Kymera Therapeutics employee. ©2022 KY MERA T
Slide 3: Proteome Editing with Targeted Protein Degradation
Proteome Editing with Targeted Protein Degradation A Nobel Prize (2004) Inspired Technology Targeted Small Expanded Opportunities Disease-causing Molecule 1 Target Protein 2 Protein Degraders • Small molecule binds to E3 and target protein to affect its degradation Degrader • Small Molecule only nee
Slide 4: Overview of STAT3 Biology
Overview of STAT3 Biology IMMUNITY VASCULATURE • STAT3 is an undruggable transcription factor Leukocyte Recruitment and Retention • STAT3 is activated by multiple tyrosine kinases and plays a Endothelial Activation critical role in the signaling of cytokines, hormones, and Leukocyte Activation growt
Slide 5: KTX-115 Selectively and Potently Degrades STAT3 in Human PBMC and Whole Blood
KTX-115 Selectively and Potently Degrades STAT3 in Human PBMC and Whole Blood KTX-115 Selectively Degrades STAT3 in KTX-115 Potently Degrades STAT3 Human huPBMC (24 h Treatment) Whole Blood (24 h Treatment) Monocytes -log 10 pvalue DC50: 0.9 nM KTX-115 25 nM (~DC95) / DMSO Average KTX-115 Concentrat
Slide 6: PBMC STAT3 Phosphorylation is Abrogated by STAT3 Degradation
PBMC STAT3 Phosphorylation via Multiple Inflammatory Stimuli is Abrogated by STAT3 degradation No stim LPS IL-6 IL-21 IL-23 0% 18.3% 41.8% 61.5% 20.2% % cells pSTAT3-positive LPS IL-6 IL-21 IL-23 LPS IL-6 IL-21 IL-23 pSTAT3 (% of DMSO control) pSTAT3 (% of DMSO control) 120 120 pSTAT3 (% of DMSO con
Slide 7: STAT3 Degradation Abrogates Phosphorylation and MCP-1/CCL2 Release More Potently than JAK Inhibition
STAT3 Degradation Abrogates STAT3 Phosphorylation and MCP-1/CCL2 Release by Human Monocytes More Potently than JAK Inhibition IL-6 stim (CD14+ Monocytes) • Primary human monocytes or THP-1 KTX-115 monocytes were pre- Ruxolitinib treated with KTX-115 45-fold 150-fold (20h) or Ruxolitinib (30 min) and
Slide 8: STAT3 Degradation Inhibits CD4+ Th17 Development and Related Cytokine Production
STAT3 Degradation Inhibits CD4+ Th17 Development and Related Cytokine Production CD3/CD28/Th17 Cocktail + CD4 T Cells (Day 7) Cytokine Release by Th17 Cells (Day 7) KTX-115 KTX-115 • CD4+ naïve T cells isolated from huPBMC were treated overnight with KTX-115 before activation with aCD3/CD28 coated b
Slide 9: STAT3 Degradation Modulates Inflammation-induced Adhesion of Blood Leukocytes to the Endothelium
STAT3 Degradation Modulates Inflammation-induced Adhesion of Blood Leukocytes to the Endothelium Blood Cells Adhering to Endothelial Cells in Shear Flow LPS-induced PBMC Adhesion (24h) LPS, vehicle LPS, 2 nM KT-6955 KTX-115 LPS, 10 nM KT-6955 KTX-115 Distler/UZH-UCJM collaboration **** p<0.0001 ©202
Slide 10: STAT3 Degradation Prevents Collagen Induced Arthritis
STAT3 Degradation Prevents Collagen Induced Arthritis Left fore paw IL-1 Collagen-induced Arthritis (BIW) Pathology Score 25 Left paw IL-1β (pg/mL) 12 20 Vehicle 10 Sum of scores 4 2 mg/kg KTX-115 15 7 mg/kg KTX-115 8 20 mg/kg KTX-115 6 10 ** 30 mg/kg Tofacitinib 4 *** Clinical scores 3 5 **** ****
Slide 11: Summary
Summary • Kymera has developed highly potent and selective degraders of STAT3 • STAT3 degradation abrogates activation by multiple inflammatory stimuli in PBMC, monocytes, and CD4+ T cells • Even limited degradation of STAT3 results in significant inhibition of cytokines involved in inflammation in
Slide 12: Thank you
Thank you Przemyslaw Blyszczuk Filip Rolski Amela Hukara Elena Pachera Gabriela Kania Vanessa Tela Oliver Distler [email protected] [email protected] [email protected] ©2022 KY MERA T HERAP EUT ICS, INC. P AGE 12
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