Slide 1: PRT2527 is a potent and selective CDK9 inhibitor with anti-cancer activity
PRT2527 is a potent and selective CDK9 inhibitor that demonstrates anti- cancer activity in preclinical models of hematological malignancies and solid tumors with MYC amplification Yang Zhang, PhD,1 Liang Lu, PhD, 1 Min Wang, PhD, 1 Dave Rominger, BS, 1 Stefan Ruepp, PhD, 1 Kirsten Gallagher, BS, 1
Slide 2: Introduction
Introduction ▪ CDK9 phosphorylates RNA Pol II and regulates transcription ▪ Regulates expression of several immediate early genes driving oncogenesis and resistance (i.e. MYC, MYB, MCL1) ▪ Non-selective CDK9 inhibitors have demonstrated clinical activity in multiple tumor types but poor tolerability
Slide 3: PRT2527 is a Potent and Selective CDK9 Inhibitor
PRT2527 is a Potent and Selective CDK9 Inhibitor A B • PRT2527 is a potent CDK9 inhibitor with a biochemical IC50 value of 0.98 nM at 1 mM ATP and a protein binding adjusted potency of 198 nM determined by a human plasma In Cell Western (ICW) assay • PRT2527 is highly selective among CDK family memb
Slide 4: Treatment Depletes MCL1, MYC, and Induces Apoptosis In Vitro and In Vivo
PRT2527 Treatment Depletes MCL1, MYC, and Induces Apoptosis In Vitro and In Vivo A B 4 MCL1 • PRT2527 depletes pSer2RNAP2 and onco-proteins FYTTD1 3 - Log10 (q value) with short half-lives such as MCL1, MYC, and 2 induces apoptosis in a dose-dependent manner in MV-4-11 cells after 4 hours treatment
Slide 5: Induces Cell Death in Hematological and Solid Tumor Models In Vitro and Ex Vivo
PRT2527 Induces Cell Death in Hematological and Solid Tumor Models In Vitro and Ex Vivo A PRT2527 Heme panel subtypes B PRT2527 ALL PDX models, ex vivo 24h CTG 2D CTG ALL AML CML Burkitt's DLBCL MCL HL PRT2527 anti-proliferative potencies in 1 T-ALL 1 B-ALL hematological (A) and solid tumor cell lin
Slide 6: Efficacious in CDX and PDX Models of Heme and Solid Tumors with MYC Alterations
PRT2527 is Efficacious in CDX and PDX Models of Heme and Solid Tumors with MYC Alterations A AML: MV-4-11 CDX B DH DLBCL: Karpas-422 CDX E 3000 Vehicle 2000 Vehicle MYC translocation Model # Tumor type MYC alter. TGI (%) PRT1122 10 mg/kg, iv, BID (q2h), 2on/5off PRT2527, 15 mg/kg, iv, BID (q2h), 2on
Slide 7: Reduces MYC Transcriptional Activity in a CRPC MYC-Reporter Model
PRT2527 Reduces MYC Transcriptional Activity in a CRPC MYC-Reporter Model In Vitro and In Vivo A DU145_reporterMyc B C D ✱✱✱✱ Avg Radiance [p/s/cm²/sr] 8000 ✱✱✱✱ 2000 Vehicle 0 4 24 Time (h) 25000 ✱ Avg Radiance [p/s/cm²/sr] ✱✱✱ PRT2527 Tumor Volume (mm3) 6000 20000 1500 Luminescence 15000 @ 30 mg/k
Slide 8: Significant Survival Benefit of PRT2527 in Responsive Pancreatic and Gastroesophageal PDX Models
Significant Survival Benefit of PRT2527 in Responsive Pancreatic and Gastroesophageal PDX Models with MYC Amplification A PNX-0001 PDAC PDX B PNX-0019 Esophageal PDX MYC amp. (13x) MYC amp (36x) 100 Probability of Survival 100 Probability of Survival UD 75 75 38 28.5 38 * 50 50 25 Vehicle 25 Vehicle
Slide 9: Conclusions
Conclusions ▪ PRT2527 is a potent and highly selective CDK9 inhibitor ▪ PRT2527 treatment depletes oncogenic drivers with short half-lives such as MYC and MCL1 and induces apoptosis ▪ Intermittent IV administration of PRT2527 demonstrated strong efficacy in hematological malignancies and solid tumor