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731925 occurrences (No.6 in the rank) during 5 years in the PubMed. [cache]

305) Increased Bak expression was correlated with poor prognosis of NSCLC patients, suggesting that Bak protein is an attractive target for lung cancer therapy.

--- ABSTRACT ---

PMID:34373755 DOI:10.7150/thno.60349

2021 Theranostics

* Discovery of Small Molecule Bak Activator for Lung Cancer Therapy.

- Rationale: Bak is a major proapoptotic Bcl2 family member and a required molecule for apoptotic cell death. High levels of endogenous Bak were observed in both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) cell lines. Increased Bak expression was correlated with poor prognosis of NSCLC patients, suggesting that Bak protein is an attractive target for lung cancer therapy. The BH3 domain functions as death domain and is required for Bak to initiate apoptotic cell death. Thus, the BH3 domain is attractive target for discovery of Bak agonist. Methods: The BH3 death domain binding pocket (aa75-88) of Bak was chosen as a docking site for screening of small molecule Bak activators using the UCSF DOCK 6.1 program suite and the NCI chemical library (300,000 small molecules) database. The top 500 compounds determined to have the highest affinity for the BH3 domain were obtained from the NCI and tested for cytotoxicity for further screening. We identified a small molecule Bak activator BKA-073 as the lead compound. The binding affinity of BKA-073 with Bak protein was analyzed by isothermal titration calorimetry (ITC) assay. BKA-073-mediated Bak activation via oligomerization was analyzed by a cross-linking with Bis (maleimido) hexane (BMH). Sensitivity of BKA-073 to lung cancer cells in vitro was evaluated by dynamic BH3 profiling (DBP) and apoptotic cell death assay. The potency of BKA-073 alone or in combination with radiotherapy or Bcl2 inhibitor was evaluated in animal models. Results: We found that BKA-073 binds Bak at BH3 domain with high affinity and selectivity. BKA-073/Bak binding promotes Bak oligomerization and mitochondrial priming that activates its proapoptotic function. BKA-073 potently suppresses tumor growth without significant normal tissue toxicity in small cell lung cancer (SCLC) and NSCLC xenografts, patient-derived xenografts, and genetically engineered mouse models of mutant KRAS-driven cancer. Bak accumulates in radioresistant lung cancer cells and BKA-073 reverses radioresistance. Combination of BKA-073 with Bcl-2 inhibitor venetoclax exhibits strong synergy against lung cancer in vivo. Conclusions: Development of small molecule Bak activator may provide a new class of anticancer agents to treat lung cancer.

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(1)186 of	(8)11 by	(15)4 as	(22)2 enable
(2)36 in	(9)10 Quantitative	(16)3 increased	(23)2 for
(3)34 and	(10)7 data	(17)3 level	(24)2 or
(4)30 null	(11)6 is	(18)3 signatures	(25)2 patterns,
(5)15 levels	(12)6 quantitative	(19)3 system	(26)2 were
(6)14 was	(13)5 patterns	(20)2 across	(27)2 which
(7)13 analysis	(14)5 profiles	(21)2 can

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--- WordNet output for expression --- =>表現すること, 式, 表現, 表示, 言い回し, 表現法, 表情 Overview of noun expression The noun expression has 9 senses (first 6 from tagged texts) 1. (23) expression, look, aspect, facial expression, face -- (the feelings expressed on a person's face; "a sad expression"; "a look of triumph"; "an angry face") 2. (18) expression, manifestation, reflection, reflexion -- (expression without words; "tears are an expression of grief"; "the pulse is a reflection of the heart's condition") 3. (15) expression, verbal expression, verbalism -- (the communication (in speech or writing) of your beliefs or opinions; "expressions of good will"; "he helped me find verbal expression for my ideas"; "the idea was immediate but the verbalism took hours") 4. (5) saying, expression, locution -- (a word or phrase that particular people use in particular situations; "pardon the expression") 5. (4) formulation, expression -- (the style of expressing yourself; "he suggested a better formulation"; "his manner of expression showed how much he cared") 6. (4) formula, expression -- (a group of symbols that make a mathematical statement) 7. expression -- ((genetics) the process of expressing a gene) 8. construction, grammatical construction, expression -- (a group of words that form a constituent of a sentence and are considered as a single unit; "I concluded from his awkward constructions that he was a foreigner") 9. expression -- (the act of forcing something out by squeezing or pressing; "the expression of milk from her breast") --- WordNet end ---