Author: Souers, Andrew J. ; Catron, Nathaniel ; Ralston, Sherry L. ; Xiao, Yu ; Wang, Xilu ; Kalvass, John C. ; Palma, Joann ; Judge, Russell A. ; Nelson, Lorne ; Song, Xiaohong ; Peterson, Richard ; Zhang, Xinxin ; Nimmer, Paul ; Henriques, Tracy A. ; Izeradjene, Kamel ; Durbin, Kenneth R. ; Doherty, George ; Shen, Xiaoqiang ; Buck, Wayne R. ; Kunzer, Aaron ; Leverson, Joel D. ; Jenkins, Gary J. ; Bawa, Bhupinder ; Mitten, Michael J. ; Tao, Zhi-Fu ; Enright, Brian ; Phillips, Darren C. ; Zhang, Haichao ; Haman, Sandra ; Judd, Andrew S. ; Wang, Jin ; Holms, James ; Li, Yingchun ; Haasch, Deanna ; Bruncko, Milan ; Martin, Ruth L. ; Phillips, Andrew ; Boghaert, Erwin R. ; Frey, Robin ; Blomme, Eric A. ; Mittelstadt, Scott ; Haight, Anthony R. ; Rosenberg, Saul H. ; Vaidya, Kedar S. ; Mitra, Diya

Overexpression of the antiapoptotic protein B-cell lymphoma-extra large (BCL-X L ) is associated with drug resistance and disease progression in numerous cancers. The compelling nature of this protein as a therapeutic target prompted efforts to develop selective small-molecule BCL-X L inhibitors. Although efficacious in preclinical models, we report herein that selective BCL-X L inhibitors cause severe mechanism-based cardiovascular toxicity in higher preclinical species. To overcome this liability, antibody-drug conjugates were constructed using altered BCL-X L –targeting warheads, unique linker technologies, and therapeutic antibodies. The epidermal growth factor receptor–targeting antibody-drug conjugate AM1-15 inhibited growth of tumor xenografts and did not cause cardiovascular toxicity nor dose-limiting thrombocytopenia in monkeys. While an unprecedented BCL-X L –mediated toxicity was uncovered in monkey kidneys upon repeat dosing of AM1-15, this toxicity was mitigated via further drug-linker modification to afford AM1-AAA (AM1-25). The AAA drug-linker has since been incorporated into mirzotamab clezutoclax, the first selective BCL-X L –targeting agent to enter human clinical trials.

01 Aug 2003·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

In Vitro Activities of Novel Oxapenems, Alone and in Combination with Ceftazidime, against Gram-Positive and Gram-Negative Organisms

Q2 · MEDICINE

Article

Author: Lambert, Peter A. ; Simpson, Iain N. ; Jamieson, Conor E.

ABSTRACT Four novel oxapenem compounds (i.e., AM-112, AM-113, AM-114, and AM-115) were investigated for their β-lactamase inhibitory activity against a panel of isolated class A, C, and D enzymes, which included expanded-spectrum β-lactamase enzymes (ESBLs). The oxapenems were potent β-lactamase inhibitors. Activity varied within the group, with AM-113 and AM-114 proving to be the most active compounds. The 50% inhibitory concentrations for these agents were up to 100,000-fold lower than that of clavulanic acid against class C and D enzymes. As a group, the oxapenems were more potent than clavulanic acid against enzymes from all classes. The ability of these compounds to protect ceftazidime from hydrolysis by β-lactamase-producing strains was evaluated by MIC tests that combined ceftazidime and each oxapenem in a 1:1 or 2:1 ratio. The oxapenems markedly reduced the MICs for ceftazidime against class C hyperproducing strains and strains producing TEM- and SHV-derived ESBLs. There was little difference between the activity of 1:1 and 2:1 combinations of ceftazidime and oxapenem. The oxapenems failed to enhance the activity of ceftazidime against derepressed AmpC-producing Pseudomonas aeruginosa strains.

01 Jan 2003·The Journal of AntibioticsQ4 · MEDICINE

Synthesis and Biological Activity of AM-112 and Related Oxapenem Analogues

Q4 · MEDICINE

Article

Author: Gudrun Hagen ; Hans R. Pfaendler ; Birgit Sprinkart ; Christopher J. Urch ; Ralf Albrecht ; Iain N. Simpson

Thirty five oxapenem analogues substituted with a range of tertiary groups at C-2 have been synthesised and evaluated as broad-spectrum beta-lactamase inhibitors. All analogues enhanced the activity of ceftazidime against bacterial isolates producing Class A and Class C beta-lactamases. Compounds with cyclic substituents at C-1' (attached to C-6) were associated with enhanced antibacterial activity against Staphylococcus aureus. (R) Stereochemistry at C-1' led to synergistic activity against beta-lactamase negative enterococci. (S) Stereochemistry at C-1' was associated with enhanced inhibition of Class A beta-lactamases and lack of synergistic activity against enterococci. AM-113 was unstable in serum and not detectable following subcutaneous or oral dosing in mice. AM-112 and AM-115 achieved good serum levels following subcutaneous dosing. AM-114 exhibited 30% bioavailability following oral dosing. AM-112 [(1'R,5R,6R)-2-(4-ammonio-1,1-dimethylbutyl)-6-(1'-hydroxyethyl)oxapenem-3-carboxylate] achieved the greatest protection of ceftazidime against Gram-negatives producing Class A or C beta-lactamases.

100 Deals associated with AM-115

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Indication	Highest Phase	Country/Location	Organization	Date
Gram-Negative Bacterial Infections	Preclinical	United Kingdom	University of Aston	10 May 2003
Gram-Positive Bacterial Infections	Preclinical	United Kingdom	University of Aston	10 May 2003

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