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Non-small cell lung cancer (NSCLC) continues to be a leading cause of cancer death. Its fatality is associated with angiogenesis and metastasis. While VEGFR inhibitors are expected to be the central pillar for halting lung cancer, several clinical reports declared their subpar activities as monotherapy. These results directed combination studies of VEGFR inhibitors, especially sorafenib (Nexavar®), with various chemotherapeutic agents. Matrix metalloproteinase (MMP) inhibitors are seldom utilized in such combinations despite the expected complementary therapeutic outcome. This could be attributed to the clinical unsuitability of MMP inhibitors from the hydroxamate family. Herein, we report new non-hydroxamate s-triazinedione-based inhibitors of MMP-9 (6b; IC 50  = 0.112 μM), and MMP-10 (6e; IC 50  = 0.076 μM) surpassing the hydroxamate inhibitor NNGH for chemosensitization of NSCLC to sorafenib. MMPs inhibition profiling of the hits revealed MMP-9 over -2 and MMP-10 over -13 selectivity. 6b and 6e were potent (IC 50  = 0.139 and 0.136 µM), safe (SI up to 6.77) and superior to sorafenib (IC 50  = 0.506 µM, SI = 6.27) against A549 cells. When combined with sorafenib, the studied MMP inhibitors enhanced its cytotoxic efficacy up to 26 folds as confirmed by CI and DRI values for 6b (CI = 0.160 and DRI = 22.175) and 6e (CI = 0.096 and DRI = 29.060). 6b and 6e exerted anti-invasive activities in A549 cells as single agents (22.66 and 39.67 %) and in sorafenib combinations (29.96 and 91.83 %) compared to untreated control. Both compounds downregulated VEGF in A549 cells by approximately 70 % when combined with sorafenib, highlighting enhanced anti-angiogenic activities. Collectively, combinations of 6b and 6e with sorafenib demonstrated synergistic NSCLC cytotoxicity with pronounced anti-invasive and anti-angiogenic activities introducing a promising start point for preclinical studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)