Renal dipeptidase (EC 3.4.13.11) was solubilized from pig kidney microvillar membranes with bacterial phosphatidylinositol-specific phospholipase C and then purified by affinity chromatography on cilastatin-Sepharose. The enzyme was apparently homogeneous on SDS/polyacrylamide-gel electrophoresis with an Mr of 47,000. Immunohistochemical analysis of the distribution of the dipeptidase showed it to be concentrated in the brush-border region of the proximal tubules in close association with endopeptidase-24.11) (EC 3.4.24.11). The purified dipeptidase was shown to contain 1 mol of inositol/mol and to possess the cross-reacting determinant characteristic of the glycosyl-phosphatidylinositol membrane-anchoring domain. The glycoprotein nature of renal dipeptidase was confirmed by chemical and enzymic deglycosylation. These results establish renal dipeptidase as a glycosyl-phosphatidylinositol-anchored ectoenzyme of the microvillar membrane.

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3085 Background: BRD4 is a bromodomain and extraterminal (BET) protein that regulates oncogenic programs by modifying gene transcription and additional mechanisms. AZD5153 is a novel, reversible BRD4 inhibitor with bivalent mechanism of action and enhanced antitumor activity in preclinical models. This phase 1, multicenter, dose escalation study (NCT03205176) assesses AZD5153’s safety, pharmacokinetics (PK), and pharmacodynamics (PD). We report here preliminary, unvalidated data from AZD5153 monotherapy in pts with RR solid tumor, including lymphoma. Methods: Adult pts received oral AZD5153 QD/BID to determine the MTD. During dose escalation, a continual reassessment model was used to estimate toxicity and all final decisions were made by the Safety Review Committee. PK and PD were characterized using standard methods. Results: As of 1 Nov 2018, 28 pts (78.6% female, median age 66.5 y) were treated in 7 cohorts: 2 mg QD (3 pts), 5 mg QD (3 pts), 10 mg QD (3 pts), 10 mg BID (5 pts), 15 mg BID (4 pts), 20 mg BID (7 pts), and 30 mg QD (3 pts). Treatment was ongoing in 8 pts at data cut-off. Safety findings showed 50% of pts experienced treatment-related AEs. 25% of pts experienced treatment-related Grade ≥3 AEs, which were thrombocytopenia and fatigue (7.1% each), and anemia, diarrhea, and platelet count decreased (3.6% each). SAEs were observed in 25% of pts; none of the SAEs was attributable to AZD5153 alone. Dose-limiting toxicities of thrombocytopenia (1 pt) and diarrhea with herpetic rash leading to discontinuation (1 pt) occurred at 20 mg BID. 53.6% of pts discontinued due to disease progression. Total median treatment duration was 1.3 mo (range up to 8.9 mos). Dose proportional increase in Cmax and AUC were observed across the dose range tested. Tmax ranged from 0.5 to 3 h and t1/2 was 6 h. Dose-dependent changes in expression of target genes (eg, HEXIM1, HIST2H2BF, CD274, and CCR2) and platelet counts were observed in the peripheral blood. Conclusions: AZD5153 monotherapy is safe and tolerated at doses up to 30 mg QD and 15 mg BID. Linear increase in PK was observed. Additional safety and efficacy updates will be reported at the annual meeting. Clinical trial information: NCT03205176.

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