Abstract: This disclosure describes embodiments of selective and potent CDK 4/6 inhibitors that show advantageous inhibition of cancer growth, even at low concentrations. As described herein, compounds of the present approach comprise substituted pyridinylpiperazine-pyrrolopyrimidine compounds having a fatty acid moiety. The compounds described herein may be used as pharmaceutical compounds for anti-cancer therapies, and are useful for the treatment, prevention and/or amelioration of cancer.

Abstract: This disclosure describes the use of azithromycin, roxithromycin, and telithromycin, including derivatives thereof, as senolytic drugs. BrdU was used to induce senescence in model human fibroblast cell lines. Also disclosed are methods for screening compounds for senolytic activity. The SRB assay was used to measure cell viability through protein content. Azithromycin roxithromycin, and telithromycin, clinically-approved pharmaceuticals, were found to be senolytic drugs. However, the closely-related parent compound, erythromycin, showed no senolytic activity. Azithromycin strongly induced both aerobic glycolysis and autophagy in human fibroblasts, but showed bi-phasic effects including on mitochondrial oxygen consumption rates with inhibitory activity at 50 ?M and stimulatory activity at 100 ?M. The xCELLigence real-time assay system showed that azithromycin preferentially targets senescent cells, removing approximately 97% (nearly a 25-fold reduction in senescent cells).

Abstract: This disclosure describes embodiments of selective and potent CDK 4/6 inhibitors that show advantageous inhibition of cancer growth, even at low concentrations. As described herein, compounds of the present approach comprise substituted pyridinylpiper-azine-pyrrolopyrimidine compounds having a fatty acid moiety. The compounds described herein may be used as pharmaceutical compounds for anti-cancer therapies, and are useful for the treatment, prevention and/or amelioration of cancer.

Abstract: The present approach effectively eradicates senescent cells and cells carrying the hallmarks associated with aging, through inhibiting mitochondrial biogenesis during induced mitochondrial oxidative stress, without inhibiting normal cells. Embodiments may include a therapeutic agent that inhibits mitochondrial biogenesis and targets the large mitochondrial ribosome, a therapeutic agent that inhibits mitochondrial biogenesis and targets the small mitochondrial ribosome, and a therapeutic agent that behaves as a pro-oxidant or induces mitochondrial oxidative stress. Some embodiments include sub-antimicrobial antibiotic concentrations, thereby minimizing antibiotic resistance concerns.

Abstract: High ATP production by the mitochondrial ATP-synthase is a new therapeutic target for anti-cancer therapy, especially for preventing tumor progression. A mitochondrial-related gene signature for metastasis is described, which features the gamma-subunit of the mitochondrial ATP-synthase (ATP5F1C). Knock-down of ATP5F1C expression significantly reduces ATP-production, 3D anchorage-independent growth and cell migration. Administration of the Bedaquiline, or a Bedaquiline derivative with a fatty acid moiety, down-regulates ATP5F1C expression in vitro and prevents spontaneous metastasis in vivo. Mitochondrial ATP5F1C is a promising new biomarker and molecular target for future drug development, for the prevention of metastatic disease progression.

Abstract: The present disclosure relates to compounds and methods of eradicating cancer stem cells by combining inhibitors of oxidative metabolism and glycolytic metabolism. Also described are compounds and methods of identifying a combination of inhibitors of oxidative metabolism and glycolytic metabolism to treat cancer stem cells.

Abstract: Antibiotics having intrinsic anti-mitochondrial properties may be chemically modified to target the antibiotics to mitochondria, and the resulting “antimitoscins” may have enhanced anti-cancer properties, among other advantageous properties. Also described are methods for identifying antimitoscins, methods of using antimitoscins to target cancer stem cells, and pharmaceutical compositions for treating cancer containing one or more antimitoscins as the active ingredient. Specific antimitoscins compounds and groups of antimitoscins are also disclosed.

Abstract: Tri-phenyl-phosphonium (TPP) is a non-toxic chemical moiety that functionally behaves as a mitochondrial targeting signaling in living cells. TPP-related compounds may be utilized to target mitochondria in cancer stem cells (CSC5), and may be used for treating and/or preventing tumor recurrence, metastasis, drug resistance, and/or radiotherapy resistance, as well as for anticancer therapies. Various TPP-related compounds validated for oxygen consumption inhibition (OCR), were non-toxic, and had little or no effect on ATP production in normal human fibroblasts. Yet these compounds selectively target adherent “bulk” cancer cells. These compounds also inhibit the propagation of CSCs in suspension. TPP-related compounds provide a novel chemical strategy for effectively targeting both i) “bulk” cancer cells and ii) CSCs, while specifically minimizing or avoiding off-target side-effects in normal cells, among other useful therapies.

Abstract: This disclosure describes embodiments of selective and potent CDK 4/6 inhibitors that show advantageous inhibition of cancer growth, even at low concentrations. As described herein, compounds of the present approach comprise substituted pyridinylpiper-azine-pyrrolopyrimidine compounds having a fatty acid moiety. The compounds described herein may be used as pharmaceutical compounds for anti-cancer therapies, and are useful for the treatment, prevention and/or amelioration of cancer.

Abstract: MCF7-fibroblast co-cultures are a valuable model of resistance to apoptosis induced by hormonal therapies, such as Tamoxifen and Fulvestrant. These mixed co-cultures demonstrate the induction of mito-sternness and ribo-stemness features. Molecular therapeutic targets were identified through label-free proteomics of MCF7-fibroblast co-cultures, and independently validated using a bioinformatics approach. The resulting Mito-Signature is prognostic of endocrine treatment failure, tumor recurrence, and distant metastasis, and may be used to identify patients at risk of treatment failure. Such patients may be treated with a mitochondrial biogenesis inhibitor to reduce the risk of treatment failure, and/or to increase the effectiveness of the hormone therapy.

Abstract: Disclosed are 9-amino-doxycycline derivatives that target cancer stem cells and inhibit cancer metastasis. These compounds selectively target CSCs, potently inhibit tumor cell metastasis in vivo, with little or no toxicity, and minimize the risk of driving antibiotic resistance. In one embodiment, a 14 carbon fatty acid moiety is covalently attached to the free amino group of 9-amino-doxycycline. The resulting “Doxy-Myr” conjugate is over 5-fold more potent than doxycycline for inhibiting the anchorage-independent growth of MCF7 CSCs. Doxy-Myr did not affect the viability of the total MCF7 cancer cell population or normal fibroblasts grown as 2D-monolayers, showing remarkable selectivity for CSCs. Doxy-Myr did not show antibiotic activity, against Escherichia coli and Staphylococcus aureus. Conjugates having either longer (16 carbon; palmitic acid) or shorter (12 carbon; lauric acid) fatty acid chain lengths had similar activity.

Abstract: Cancer stem cells are responsible for tumor recurrence, distant metastasis and drug-resistance, in the vast majority of cancer patients. There exists an urgent need to identify new mitochondrial inhibitor drugs that can target and eradicate CSCs, and companion diagnostics to identify candidates for mitochondrial inhibition therapy. In 3D mammospheres, 25 mitochondrial-related proteins were over 100-fold over-expressed in a large collection of transcriptional profiling data from ER(+) breast cancer patients. These 25 proteins may be used to derive short gene signatures to predict the likelihood of distant metastasis and tumor recurrence. For example, the 4-gene signature of ACLY, VDAC3, HADH2, and COX6B1 may be used for predicting the likelihood of distant metastasis, with a hazard ratio of 1.91-fold (P=2.2e?08). A pharmaceutically effective amount of a mitochondrial inhibitor may be administered to a candidate having elevated expression of the genes in a gene signature.

Abstract: The present disclosure relates to compounds that bind to at least one of ACAT1/2 and OXCT1/2 and inhibit mitochondrial ATP production, referred to herein as mitoketoscins. Methods of screening compounds for mitochondrial inhibition and anti-cancer properties are disclosed. Also described are methods of using mitoketoscins to prevent or treat cancer, bacterial infections, and pathogenic yeast, as well as methods of using mitoketoscins to provide anti-aging benefits. Specific mitoketoscin compounds are also disclosed.

Abstract: The present disclosure relates to compounds that bind to at least one of ACAT1/2 and OXCT1/2 and inhibit mitochondrial ATP production, referred to herein as mitoketoscins. Methods of screening compounds for mitochondrial inhibition and anti-cancer properties are disclosed. Also described are methods of using mitoketoscins to prevent or treat cancer, bacterial infections, and pathogenic yeast, as well as methods of using mitoketoscins to provide anti-aging benefits. Specific mitoketoscin compounds are also disclosed.

Abstract: This disclosure describes selective and potent CDK 4/6 inhibitors that show advantageous inhibition of cancer growth, even at low concentrations. This class of anti-cancer CDK 4/6 inhibitors are substituted pyrrolopyrimidine compounds of formula IA, having a fatty acid moiety. These compounds may be used as pharmaceutical compounds for anti-cancer therapies, and are useful for the treatment, prevention and/or amelioration of cancer.

Abstract: The disclosure describes selective and potent CDK 4/6 inhibitors that show advantageous inhibition of cancer growth, even at low concentrations. A class of the CDK 4/6 inhibitors relates to substituted pyridopyrimidines compounds having a fatty acid moiety, and are namely derivatives of Palbociclib of general formula [2A], wherein R1 is hydrogen, aryl, alkyl, alkoxy, cycloalkyl, or heterocyclyl; R2 is hydrogen, halogen, alkyl, acyl, cycloalkyl, alkoxy, alkoxy alkyl, haloalkyl, hydroxy alkyl, alkenyl, alkynyl, nitrile, or nitro; R3 is hydrogen, halogen, alkyl, haloalkyl, hydroxy alkyl, or cycloalkyl; and n is an integer from 9 to 20. These compounds may be used as pharmaceutical compounds for anti-cancer therapies, and are useful for the treatment, prevention and/or amelioration of cancer.

Abstract: This disclosure describes the characteristics of the “energetic” cancer stem cell (e-CSC) phenotype. This distinct sub-population of cancer stem cells (CSCs) has a unique energetic profile compared to bulk CSCs, being more glycolitic, having higher mitochondrial mass and elevated oxidative metabolism. e-CSCs also show an increased capacity to undergo cell cycle progression, enhanced anchorage-independent growth, and ALDH-positivity. The e-CSC phenotype presents new targets for cancer therapeutics, and in particular the anti-oxidant response, mitochondrial energy production, and mitochondrial biogenesis of e-CSCs makes them highly susceptible to mitochondrial inhibitors that target e-CSC anti-oxidant response, mitochondrial energy production, and mitochondrial biogenesis. Gene products for e-CSCs are disclosed, as well as classes of mitochondrial inhibiting therapeutic agents. Also disclosed are methods for identifying and separating e-CSCs front bulk cell populations.

Abstract: The present disclosure relates to a Proteomics-to-Genomics approach allows for in silico validation of biomarkers and drug targets. Biomarkers having high prognostic value in predicting cancer patient populations that may benefit from mitochondrial biogenesis inhibitor therapy may be identified under the present approach. Also disclosed are methods for identifying candidates for anti-mitochondrial therapy, and in particular mitochondrial biogenesis inhibitor therapy. Diagnostic kits including reagents for determining transcripts or probes of high prognostic value are also disclosed. Additionally, mitochondrial biogenesis inhibitors may be used as anti-cancer agents for diverse oncogenic stimuli, including for example, c-MYC and H-Ras oncogenes, as well as environmental stimuli such as, for example rotenone.

Abstract: Derivatives of mDIVI-1 may be used to target and eliminate cancer stem cells. Disruption in the mitochondrial dynamics balance plays a role in cancer. Proteins involved in regulating mitochondrial dynamics represent potential targets for cancer treatment. Mitochondrial fission protein DRP1 is such a target. Derivatives of mDIVI-1 inhibit DRP1, and have demonstrated inhibition of tumorsphere forming capacity, migration and stemness-related signaling in breast cancer cells. These properties result from induction of mitochondrial oxidative stress and reduction of mitochondrial metabolism in the target cancer cells. The potency of an mDIVI-1 derivative may be dramatically increased through addition of at least one membrane-targeting signal and/or a mitochondria-targeting signal.

Abstract: The present disclosure relates to inhibitors of mitochondrial function. Methods of screening compounds for mitochondrial inhibition are disclosed. Also described are methods of using mitochondrial inhibitors called mitoriboscins—mitochondrial-based therapeutic compounds having anti-cancer and antibiotic properties—to prevent or treat cancer, bacterial infections, and pathogenic yeast, as well as methods of using mitochondrial inhibitors to provide anti-aging benefits. Specific mitoriboscin compounds and groups of mitoriboscins are also disclosed.