The anti-apoptotic protein MCL-1 is a key regulator of cancer cell survival and a known resistance factor for small-molecule BCL-2 family inhibitors such as ABT-263 (navitoclax), making it an attractive therapeutic target. However, directly inhibiting this target requires the disruption of high-affinity protein–protein interactions, and therefore designing small molecules potent enough to inhibit MCL-1 in cells has proven extremely challenging. Here, we describe a series of indole-2-carboxylic acids, exemplified by the compound A-1210477, that bind to MCL-1 selectively and with sufficient affinity to disrupt MCL-1–BIM complexes in living cells. A-1210477 induces the hallmarks of intrinsic apoptosis and demonstrates single agent killing of multiple myeloma and non-small cell lung cancer cell lines demonstrated to be MCL-1 dependent by BH3 profiling or siRNA rescue experiments. As predicted, A-1210477 synergizes with the BCL-2/BCL-XL inhibitor navitoclax to kill a variety of cancer cell lines. This work represents the first description of small-molecule MCL-1 inhibitors with sufficient potency to induce clear on-target cellular activity. It also demonstrates the utility of these molecules as chemical tools for dissecting the basic biology of MCL-1 and the promise of small-molecule MCL-1 inhibitors as potential therapeutics for the treatment of cancer.
BackgroundSome patients (pts) with rheumatoid arthritis (RA) achieve low disease activity (LDA) after treatment with adalimumab (ADA) plus methotrexate (MTX) and can maintain LDA after ADA withdrawal1. However, others experience a flare in disease activity. The factors associated with loss or maintenance of response are not understood.ObjectivesTo identify pt disease characteristics and early clinical responses, which predict maintenance of LDA upon ADA withdrawal in individual RA pts.MethodsData from the OPTIMA trial were used in this post hoc analysis. In period 1 (P1), pts were treated for 26 weeks (wks) with ADA+MTX or placebo (PBO) +MTX. Pts on ADA+MTX who achieved DAS28-CRP <3.2 at wks 22 and 26 (responders) were randomized to ADA withdrawal, or ADA+MTX continuation up to Wk 78. Responders to PBO+MTX in P1 continued on PBO+MTX up to Wk 78 (PBO continuation). Data from the ADA withdrawal arm were used to predict LDA at Wk 78 by DAS28-CRP (≤3.2) or SDAI (≤11). Potential factors including baseline (BL) disease characteristics and Wk 26 responses, including DAS28-CRP, SDAI, ACR score components, modified total sharp score (mTSS) and joint space narrowing score (JSN), were screened by the LASSO method2, which performs variable selection by penalizing unduly complicated models, with/without incorporating the speed of DAS28-CRP or SDAI response as an individual predictor. Logistic regression on the LASSO-selected factors yielded coefficients used to derive individual scoring equations and prediction scores for Wk 78 outcomes (fig footnote). Prediction score cutoffs were established by the regression tree method3. The results were validated in data from the PBO continuation arm.ResultsFor the prediction of DAS28-CRP LDA at Wk 78, BL physician global assessment (PhGA) and health-assessment questionnaire-disability index (HAQ-DI), and Wk 26 DAS28-CRP, HAQ-DI, JSN and CRP were selected by LASSO, and used to calculate the prediction score. Including speed of response did not affect the predictors chosen. Out of 9 pts predicted not to have DAS28-CRP LDA at Wk 78, 0 had LDA (NPV=100%) (fig 1). Out of 66 pts predicted to have DAS28-CRP LDA at Wk 78, 63 predictions were correct (PPV=96.5%). Results were comparable for most cutoff categories in the validation arm (PPV=82%); however, no pts were predicted to have a non-response at Wk 78. For the prediction of SDAI LDA at Wk 78, the NPV was 86% (1/7 predictions incorrect); PPV was 95% (39/41 predictions correct); in the validation arm, the PPV was 82%.ConclusionsDAS28-CRP LDA at 78 wks could be individually predicted for up to 63% pts in OPTIMA who withdrew ADA/continued PBO+MTX with 96.5% accuracy, based on demographics and clinical outcomes at 6 months. This instrument could help identify pts who may be able to maintain LDA upon ADA withdrawal.References Smolen et al, 2013. Lancet;383.Tibshirani, R, 1996. J Royal and Stat Society; 58.Breiman L., et al, 1984. Classification and Regression Trees. Wadsworth. AcknowledgementsAbbVie: study sponsor, contributed to design, data col...
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