Therapeutic strategies to overcome taxane resistance in cancer.

Novel indazole and benzimidazole analogues were designed and synthesized as tubulin inhibitors with potent antiproliferative activities. Among them, compound 12b exhibited the strongest inhibitory effects on the growth of cancer cells with an average IC50 value of 50 nM, slightly better than colchicine. 12b exhibited nearly equal potency against both, a paclitaxel-resistant cancer cell line (A2780/T, IC50 = 9.7 nM) and the corresponding parental cell line (A2780S, IC50 = 6.2 nM), thus effectively overcoming paclitaxel resistance in vitro. The crystal structure of 12b in complex with tubulin was solved to 2.45 A resolution by X-ray crystallography, and its direct binding was confirmed to the colchicine site. Furthermore, 12b displayed significant in vivo antitumor efficacy in a melanoma tumor model with tumor growth inhibition rates of 78.70% (15 mg/kg) and 84.32% (30 mg/kg). Collectively, this work shows that 12b is a promising lead compound deserving further investigation as a potential anticancer agent.

Discovery of Novel Benzimidazole and Indazole Analogues as Tubulin Polymerization Inhibitors with Potent Anticancer Activities.

Tubulin-targeted chemotherapy has proven to be a successful and wide spectrum strategy against solid and liquid malignancies. Therefore, new ways to modulate this essential protein could lead to new antitumoral pharmacological approaches. Currently known tubulin agents bind to six distinct sites at α/β-tubulin either promoting microtubule stabilization or depolymerization. We have discovered a seventh binding site at the tubulin intradimer interface where a novel microtubule-destabilizing cyclodepsipeptide, termed gatorbulin-1 (GB1), binds. GB1 has a unique chemotype produced by a marine cyanobacterium. We have elucidated this dual, chemical and mechanistic, novelty through multidimensional characterization, starting with bioactivity-guided natural product isolation and multinuclei NMR-based structure determination, revealing the modified pentapeptide with a functionally critical hydroxamate group; and validation by total synthesis. We have investigated the pharmacology using isogenic cancer cell screening, cellular profiling, and complementary phenotypic assays, and unveiled the underlying molecular mechanism by in vitro biochemical studies and high-resolution structural determination of the α/β-tubulin-GB1 complex.

Gatorbulin-1, a distinct cyclodepsipeptide chemotype, targets a seventh tubulin pharmacological site.

Medicinal Chemistry of Indane and Its Analogues: A Mini Review

Phosphatases are a diverse family of enzymes, comprising at least 10 distinct protein folds. Like most other enzyme families, many have sequence variations that predict an impairment or loss of catalytic activity classifying them as pseudophosphatases. Research on pseudoenzymes is an emerging area of interest, with new biological functions repurposed from catalytically active relatives. Here, we provide an overview of the pseudophosphatases identified to date in all major phosphatase families. We will highlight the degeneration of the various catalytic sequence motifs and discuss the challenges associated with the experimental determination of catalytic inactivity. We will also summarize the role of pseudophosphatases in various diseases and discuss the major challenges and future directions in this field.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/febs.15431

The dead phosphatases society: a review of the emerging roles of pseudophosphatases.

Microtubule-targeting agents and their impact on cancer treatment.

Human myotubularin-related protein 9 regulates ER-to-Golgi trafficking and modulates WNT3A secretion.

Tau is an intrinsically-disordered microtubule-associated protein (MAP) implicated in neurodegenerative disease. On microtubules, tau molecules segregate into two kinetically distinct phases, consisting of either independently diffusing molecules or interacting molecules that form cohesive envelopes around microtubules. Envelopes differentially regulate lattice accessibility for other MAPs, but the mechanism of envelope formation remains unclear. Here, we find that tau envelopes form cooperatively, locally altering the spacing of tubulin dimers within the microtubule lattice. Envelope formation compacted the underlying lattice, whereas lattice extension induced tau-envelope disassembly. Investigating other members of the tau-MAP family, we find MAP2 similarly forms envelopes governed by lattice-spacing, whereas MAP4 cannot. Envelopes differentially biased motor protein movement, suggesting that tau family members could spatially divide the microtubule surface into functionally distinct segments. We conclude that the interdependent allostery between lattice-spacing and cooperative envelope formation provides the molecular basis for spatial regulation of microtubule-based processes by tau and MAP2.

https://www.biorxiv.org/content/biorxiv/early/2021/11/10/2021.11.08.467404.full.pdf

Lenka Libusova

Papers

Microtubule-targeting agents and their impact on cancer treatment.

Human myotubularin-related protein 9 regulates ER-to-Golgi trafficking and modulates WNT3A secretion.

Microtubule Lattice Spacing Governs Cohesive Envelope Formation of Tau Family Proteins