AZ-PRMT5i-1 / AstraZeneca - LARVOL DELTA

Discovery and In Vivo Efficacy of AZ-PRMT5i-1, a Novel PRMT5 Inhibitor with High MTA Cooperativity. (PubMed, J Med Chem) - "Bioisosteric replacement of the original thiazole guanidine headgroup, spirocyclization of the isoindolinone amide scaffold to both configurationally and conformationally lock the bioactive form, and fine-tuning of the potency, MTA cooperativity, and DMPK properties through specific substitutions of the azaindole headgroup were conducted. We have identified an orally available in vivo lead compound, 28 ("AZ-PRMT5i-1"), which shows sub-10 nM PRMT5 cell potency, >50-fold MTA cooperativity, suitable DMPK properties for oral dosing, and significant PRMT5-driven in vivo efficacy in several MTAP-deficient preclinical cancer models."

Journal • Preclinical • Oncology • MTAP

AstraZeneca advances scientific leadership in haematology at ASH 2023 (AstraZeneca Press Release) - "Updated Phase I data for AstraZeneca’s CD19/CD3 T-cell engager, AZD0486, will further demonstrate the acceptable safety profile and high response rate of this treatment in relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL). We will also present the first clinical data on sabestomig, a PD-1/TIM-3 targeting bispecific antibody, in R/R Hodgkin lymphoma, showing encouraging early signals of activity. The first preclinical data for AZD9829, a novel CD123-targeting ADC, using AstraZeneca’s proprietary linker technology to deliver a topoisomerase I inhibitor warhead, will demonstrate promising anti-tumour activity in acute myeloid leukaemia. In addition, preclinical data will demonstrate anti-tumour activity of AstraZeneca’s novel PRMT5 inhibitor in MTAP silenced Hodgkin lymphoma models."

P1 data • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Hodgkin Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

AZ-PRMT5i-1: A potent MTAP-selective PRMT5 inhibitor with pharmacodynamic and monotherapy anti-tumor activity in MTAP-deleted tumours (AACR 2023) - "Overall, these studies demonstrate that AZ-PRMT5i-1 is a potent PRMT5 inhibitor demonstrating MTAP selectivity and anti-tumor activity in in vitro and in vivo pre-clinical models."

Monotherapy • PK/PD data • Oncology • MTAP • PRMT5

Identification of a novel series of MTAP-selective PRMT5 inhibitors, and first disclosure of AZ-PRMT5i-1 (AACR 2023) - "AZ-PRMT5i-1 is a structurally novel and potent PRMT5 inhibitor with high MTAP-selectivity suitable for use in in vitro and in vivo PRMT5-driven models of cancer’.Note: the structure of AZ-PRMT5i-1 will be disclosed at this meetingPRMT5 Cell SDMA: IC50 nM (HCT116 MTAP KO / WT)SDMA MTAP selectivity (fold)LogD / Rat heps CLint / Caco2 intr. A-BHTS hit A660 / 43006.52.1 / 34 / 1.6AZ-PRMT5i-15.4 / 290542.8 / 5.0 / 48"

Oncology • MTAP • PRMT5

AstraZeneca advances its pipeline and highlights progress in immuno-oncology, ADCs, cell therapy and epigenetics at AACR (AstraZeneca Press Release) - "Preclinical data for AZD8205, an ADC targeting B7-H4, will also be presented both as monotherapy and in combination with the PARP-1 selective inhibitor, AZD5305. Robust anti-tumour activity is evident in preclinical models across multiple B7-H4 positive tumour types, including ovarian and cholangiocarcinoma tumours, with combination therapy resulting in higher anti-tumour activity than monotherapy....At AACR, the first preclinical data will be presented for the novel lead epigenetics molecule, AZ-PRMT5i-1, a potent methylthioadenosine phosphorylase (MTAP)-selective PRMT5 inhibitor with anti-tumour activity in MTAP-deleted tumours."

Preclinical • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor