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A main challenge in the development of new agents for the treatment of Pseudomonas aeruginosa infections is the identification of chemotypes that efficiently penetrate the cell envelope and are not susceptible to established resistance mechanisms. Siderophore-conjugated monocarbams are attractive because of their ability to hijack the bacteria's iron uptake machinery for transport into the periplasm and their inherent stability to metallo-β-lactamases. Through development of the SAR we identified a number of modifications to the scaffold that afforded active anti-P. aeruginosa agents with good physicochemical properties. Through crystallographic efforts we gained a better understanding into how these compounds bind to the target penicillin binding protein PBP3 and factors to consider for future design. KEYWORDS: Pseudomonas aeruginosa, β-lactam, penicillin binding protein, siderophore, monocarbam, structure-guided design O ne of the largest challenges in the discovery of new Gram-negative antibacterial agents is the identification of chemotypes that can penetrate the cell envelope. 1 The pathogens, such as Pseudomonas aeruginosa (P. aeruginosa), have evolved complex cell architectures including an outer membrane composed of charged lipopolysaccharides, a thin peptidogylcan layer, and an inner membrane made up of phospholipids. 2 Identifying molecules with the necessary features to enable permeation has been a challenge.β-Lactams are one chemotype that have been successful in the treatment of P. aeruginosa. 3 Since the discovery of penicillin, β-lactams have been used in the clinic and are still widely prescribed. One of the most effective classes of β-lactams for the treatment of P. aeruginosa infections are the carbapenems (e.g., meropenem, 1, Figure 1). 4 Their effectiveness stems from their ability to acylate their penicillin-binding protein (PBP) targets, aided by high permeability into P. aeruginosa through the outer membrane porins. 5 However, they are currently being challenged in the clinic by the increasing emergence of broadspectrum serine β-lactamases and metallo-β-lactamases which hydrolyze most β-lactams and render them ineffective. 6 There is one class of β-lactams that is stable to the metallo-β-lactamases: the monocyclic β-lactams represented by aztreonam (2). Aztreonam however has limited effectiveness against P. aeruginosa presumably due to its poor permeation of the outer membrane, β-lactamase susceptibility, and high propensity for efflux (P. aeruginosa MIC 90 ≥ 1024 μg/mL, n = 20 panel). 3,7 To address the poor activity of 2, we focused on improving permeation by introducing siderophore mimics to promote uptake. 8−10 Siderophores are small Fe-chelating molecules synthesized and secreted by bacteria to scavenge iron from the host. 9,11 The iron-complexed siderophores are then brought into the cell via the iron uptake machinery, enabling the bacteria to access the much needed nutrient. It has been shown that introduction of iron-chelating groups to a monocyclic β-lactam scaffold ca...

539 Background: Tinengotinib is a spectrum-selective multi-kinase inhibitor with a unique FGFR-binding mechanism. It potently inhibits FGFR2 fusion/rearrangement and acquired resistant mutations in pre-clinical models and early clinical studies in cholangiocarcinoma (CCA). Here we present the preliminary efficacy and safety of tinengotinib (TT-00420) in a phase II trial TT420C1206 (NCT04919642). Methods: Eligible patients (pts) with advanced/metastatic CCA exhausting standard treatment options received tinengotinib 10 mg QD. Pts were enrolled into four cohorts using historical FGFR alteration status: FGFR2 fusion(s) with primary progression on previous FGFR inhibitor (FGFRi) (A1) or progression after prior response to FGFRi (acquired resistance) (A2); non-fusion FGFR alteration(s) (B); or FGFR wild-type (FGFRwt, C). Primary endpoint was objective response rate (ORR) per RECIST version 1.1. Safety, PK parameters, and biomarker profile were evaluated and reviewed jointly with the efficacy outcomes. Adverse events (AEs) were graded per CTCAE version 5.0. Results: As of Sep 13, 2022, 25 pts with CCA were enrolled and dosed; 7 in A1, 6 in A2, 2 in B and 10 in C. Median age 61 [range 24-82] years old, 64% female, 93.3% had ≥ 3 prior treatment lines. 13 patients with ECOG 0 and 12 patients with ECOG 1 at baseline. Among 15 patients with historical FGFR alterations (13 fusions/rearrangement and 2 mutations), 93.3% had ≥ 1 prior FGFRi, and 3 pts (20.0%) had 2 prior FGFRi treatments. Eighteen pts were evaluable for tumor assessment at data cutoff date, including 4 in A1, 6 in A2, 1 in B and 7 in C. The median follow up was 15 weeks. In A2, 2 out of 6 pts (33%) achieved PR with tumor reductions of 34% and 54%. Overall DCR (CR or PR+SD) was 90% (9/10) in FGFR2 fusion/rearrangement pts; 100% in FGFR primary mutation pt (1/1); and 71% (5/7) in FGFRwt pts. One PR and 5 SDs lasted for more than 16 weeks. Among 25 treated pts, drug-related AEs occurred in 20 (80%) pts, including 7 (28%) with Grade (G) 1-2 AEs, 12 (48%) with G3 AEs, and 1 (4%) with G4 AE. Most frequently occurred G3/4 AEs were hypertension in 6 (24%) pts, including 5 (20%) with G3 and 1 (4%) with G4, G3 fatigue in 2 (8%) and G3 neutrophil count decreased in 2 (8%) pts. No drug-related G5 was observed. The efficacy and safety results observed were consistent with the previous reported data ( NCT03654547 ) in CCA pts. The preliminary biomarker analysis suggests loss of resistant FGFR mutation on liquid biopsy post tinengotinib therapy. Further biomarker analysis will be updated at the presentation. Conclusions: Tinengotinib may result in promising clinical benefit for CCA pts in the setting of FGFRi-resistance. Tinengotinib-related toxicities were manageable. An ongoing phase II study will further provide safety, efficacy and biomarker evaluations for both FGFR resistant and FGFRwt CCA. Clinical trial information: NCT04919642 .

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