No abstract

The prosurvival BCL2 family member MCL1 is frequently dysregulated in cancer. To overcome the signifi cant challenges associated with inhibition of MCL1 protein-protein interactions, we rigorously applied small-molecule conformational restriction, which culminated in the discovery of AMG 176, the fi rst selective MCL1 inhibitor to be studied in humans. We demonstrate that MCL1 inhibition induces a rapid and committed step toward apoptosis in subsets of hematologic cancer cell lines, tumor xenograft models, and primary patient samples. With the use of a human MCL1 knock-in mouse, we demonstrate that MCL1 inhibition at active doses of AMG 176 is tolerated and correlates with clear pharmacodynamic effects, demonstrated by reductions in B cells, monocytes, and neutrophils. Furthermore, the combination of AMG 176 and venetoclax is synergistic in acute myeloid leukemia (AML) tumor models and in primary patient samples at tolerated doses. These results highlight the therapeutic promise of AMG 176 and the potential for combinations with other BH3 mimetics. SIGNIFICANCE: AMG 176 is a potent, selective, and orally bioavailable MCL1 inhibitor that induces a rapid commitment to apoptosis in models of hematologic malignancies. The synergistic combination of AMG 176 and venetoclax demonstrates robust activity in models of AML at tolerated doses, highlighting the promise of BH3-mimetic combinations in hematologic cancers.

The development of enantioselective Lewis acid catalyzed carbonyl addition reactions of π-nucleophiles such as enolsilanes and allylstannanes is a topic of current interest. 1 The extension of this general process to include simple olefinic nucleophiles via the carbonyl-ene reaction 2 has important practical implications. In this context, Mikami and Nakai have reported a catalytic enantioselective ene reaction with glyoxylate esters; 3 however, due to the limiting reactivity of the catalyst-glyoxylate complex, 4 only nucleophilic 1,1-disubstituted olefins may be employed. We have recently reported that bidentate bis(oxazolinyl) (box) Cu(II) complexes 1-3 are effective enantioselective catalysts in Diels-Alder 5 and aldol reactions 6 with substrates that can participate in catalyst chelation. In this study, we demonstrate that these chiral Cu(II)-based Lewis acids also catalyze the enantioselective addition of a variety of olefins to glyoxylate esters 7 to provide R-hydroxy esters, versatile synthons in organic synthesis. The greater reactivity of these catalysts significantly extends the scope of this process.Initial experiments revealed that [Cu((S,S)-t-Bu-box)](SbF 6 ) 2 complex (1) 5c (10 mol %, CH 2 Cl 2 , 0 °C) promotes the addition of methylenecyclohexane to ethyl glyoxylate (eq 1) to afford (S)-4 in high enantioselectivity and yield (97% ee, 0 °C, <3 h, 97% yield). In addition, we prepared the bis(aquo) complex [Cu((S,S)t-Bu-box)(H 2 O) 2 ](SbF 6 ) 2 (2), a blue solid that is readily obtained from solutions of 1 exposed to water. 8 This complex is an equally effective catalyst with only a slight decrease in reaction rate relative to the anhydro complex 1 (eq 1, 97% ee, 0 °C, <6 h, 97%). Concurrently, it was discovered that the [Cu((S,S)-Phbox)](OTf) 2 complex (3) is also an excellent catalyst for this reaction (eq 1, 87% ee, 0 °C, 99% yield); 9 however, the absolute stereochemistry of the resulting product (R)-4 is the opposite to that produced by (S,S)-t-Bu-box catalysts 1 and 2 (vide infra). Accordingly, either enantiomer of 4 may be obtained from a single enantiomeric ligand series.The practical advantages associated with the use of the bis-(aquo) Cu(II)-box complex 2, as a readily prepared bench-stable solid, prompted us to select this catalyst for development. The reaction of ethyl glyoxylate with methylenecyclohexane (eq 1) catalyzed by 2 was found to proceed with catalyst loadings as low as 0.1 mol % without significant loss in enantioselectivity or yield (CH 2 Cl 2 , 0 °C, 24 h, g90% yield, 94% ee). This reaction may also be conducted in other solvents such as toluene and diethyl ether with no loss in enantioselectivity.The scope of the reaction of ethyl glyoxylate with other olefins has been investigated (Table 1). The t-Bu-box complex 2 (1 mol %, CH 2 Cl 2 , 0 °C) afforded excellent enantioselectivities and yields in the reactions of ethyl glyoxylate with isobutylene (5: 96% ee), R-methylstyrene (6: 93% ee), and methylenecyclopentane (7: 96% ee). 10 Catalyst 3 (10 mol %, CH 2 Cl 2 , 0 °C) also pr...

The C 2 -symmetric complexes [Cu(S,S)-tert-butylbis(oxazolinyl)](SbF6)2 (2a), its bis(aquo) counterpart [Cu(S,S)-tert-butylbis(oxazolinyl)(H2O)2](SbF6)2 (4), and [Cu(S,S)-phenylbis(oxazolinyl)](OTf)2 (1c) have been shown to catalyze the enantioselective ene reaction between glyoxylate esters and various olefins. Monosubstituted, disubstituted, and trisubstituted olefins each react with ethyl glyoxylate in the presence of 0.2−10 mol % of catalysts 1, 2, and 4 to afford the ene products in good yield and enantioselectivity. Complex 2a has also been shown to catalyze the addition of 1,1-disubstituted olefins to methyl pyruvate in good yields (76−95%) and excellent enantioselectivies (≥98% ee). The synthetic utility of the glyoxylate−ene reaction was demonstrated by conversion of the resulting α-hydroxy ester into the corresponding methyl ester, free acid, Weinreb amide, and α-azido ester, all with no detectable racemization.

The discovery and optimization of a novel series of aminoisoquinolines as potent, selective, and efficacious inhibitors of the mutant B-Raf pathway is presented. The N-linked pyridylpyrimidine benzamide 2 was identified as a potent, modestly selective inhibitor of the B-Raf enzyme. Replacement of the benzamide with an aminoisoquinoline core significantly improved kinase selectivity and imparted favorable pharmacokinetic properties, leading to the identification of 1 as a potent antitumor agent in xenograft models.