EP-4739696-A1 - MITOCHONDRIA SPECIFIC TRANSCRIPTION INHIBITOR COMPOUNDS

Abstract

Mitochondria specific transcription inhibitors may be used to target and eliminate cancer stem cells and may be used as therapeutic agents for the treatment of cancer, including reducing the likelihood of and/or preventing tumor recurrence and metastasis. The mitochondria specific transcription inhibitor compounds disclosed herein have demonstrated inhibition of tumorsphere forming capacity, migration and stemness-related signaling in cancer stem cells. These properties result from selective inhibiting of mitochondrial transcription targeting mitochondrial RNA polymerase (POLRMT) in cancer cells.

Inventors

• LISANTI, MICHAEL P.
• SOTGIA, FEDERICA
• KANGASMETSA, JUSSI
• DIPISA, Filippo

Assignees

• Lunella Biotech, Inc.

Dates

Publication Date

20260513

Application Date

20240703

Claims (1)

1. CLAIMS What is claimed is: 1. A compound having the chemical structure: , in which: • R 1 is independently selected from: -OR 1a -, -SR 1a -, -NR 1a -, -NR 1a C(O)R 1a -, -OC(O)R 1a -, - C(O)OR 1a -, -SO 2 R 1a , -S(O)R 1a -, -NR 1a C(O)-, -C(O)NR 1a -, -NR 1a S(O) 2 -, S(O) 2 NR 1a -, - OC(O)NR 1a -, -NR 1a C(O)OR 1a - , -NR 1a C(O)NR 1a -, -CR 1a =CR 1a -, -CC-, and -CH 2 R 1a -; • R 1a is independently selected from: H, alkyl, alkenyl, alkynyl, cycloalkyl heterocycloalkyl, heteroaryl or phenyl is optionally substituted where chemically allowed by from 1 to 4 groups independently selected from oxo, C 1 -C 18 -alkyl, C 2 -C 18 -alkynyl, C 2 -C 18 -alkenyl, C 1 - C 18 -haloalkyl; OR a , NR a R b , SR a , C(O)OR a , C(O)NR a R b , halo, cyano, nitro, C(O)R a , and S(O) 2 OR a ; o wherein R a is independently at each occurrence selected from: H and C 1 -C 18 - alkyl; and R b is independently at each occurrence selected from: H and C 1 -C 18 - alkyl, C(O)C 1 -C 18 -alkyl and S(O) 2 -C 1 -C 18 -alkyl; • R 2 is independently selected from a halogen, -CF 2 H, -CF 3 , -OCF 2 H, -OCF 3 , substituted or unsubstituted C5-C18 carboxyl, substituted or unsubstituted C5-C18 alkane, substituted or unsubstituted C5-C18 alkene, substituted or unsubstituted C5-C18 cyclic alkene, substituted or unsubstituted C5-C18 alkyne, substituted or unsubstituted C5-C18 ketone, substituted or unsubstituted C5-C18 aldehyde, substituted or unsubstituted C5-C18 ether, substituted or unsubstituted C5-C18 ester, substituted or unsubstituted C5-C18 amine, substituted or unsubstituted C5-C18 amide, substituted or unsubstituted C5-C18 alkyl- amide, monocyclic or polycyclic arene, heteroarene, phenol, and benzoic acid; • R 3 and R 4 may be the same or different, and are selected from H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8-cycloalkyl, substituted or unsubstituted pyridine, substituted or unsubstituted C2-C10 carboxyl, substituted or unsubstituted C2-C10 alkene, substituted or unsubstituted C2-C10 alkyne, substituted or unsubstituted C2-C10 ketone, substituted or unsubstituted C2-C10 aldehyde, substituted or unsubstituted C2-C10 ether, substituted or unsubstituted C2-C10 ester, substituted or unsubstituted C2-C10 amine, substituted or unsubstituted C2-C10 amide, substituted or unsubstituted C2-C10 alkyl-amide, substituted or unsubstituted phenol, and benzoic acid; • R 5 is selected from H, -CF 3 , -OCF 3 , -OCHF 2 , -NO 2 , and -CN; • L 1 is independently selected from: -OR 2a -, -SR 2a -, -NR 2a -, -NR 2a C(O)R 2a -, -OC(O)R 2a -, - C(O)OR 2a -, -SO 2 R 2a , -S(O)R 2a -, -NR 1a C(O)-, -C(O)NR 2a -, -NR 2a S(O) 2 -, S(O) 2 NR 2a - , - OC(O)NR 2a -, -NR 2a C(O)OR 2a - , -NR 1a C(O)NR 2a -, -CR 2a =CR 2a - and -CC-, -CH 2 R 2a -; o R 2a is independently selected from: H, alkyl, alkenyl, alkynyl, cycloalkyl heterocycloalkyl, heteroaryl or phenyl is optionally substituted where chemically allowed by from 1-4 groups independently selected from oxo, C 1 -C 6 -alkyl, C 2 -C 6 - alkynyl, C 2 -C 6 -alkenyl, C 1 -C 6 -haloalkyl; OR a , NR y R b , SR y , C(O)OR y , C(O)NRyR b , halo, cyano, nitro, C(O)Ry, S(O) 2 ORy; o wherein R y is independently at each occurrence selected from: H and C 1 -C 6 -alkyl; and R b is independently at each occurrence selected from: H and C 1 -C 6 -alkyl, C(O)C 1 -C 6 -alkyl and S(O) 2 -C 1 -C 6 -alkyl; and X- selected from a suitable anion to form a pharmaceutically acceptable salt. 2. The compound of claim 1, wherein X- is selected from the group consisting of acetate, benzenesulfonate, benzoate, besylate, bitartrate, bromide, bamsylate, chloride, citrate, decanoate, edetate, esylate, fumarate, gluceptate, hexanoate, iodide, isethionate, lactate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, propionate, salicylate, stearate, succinate, sulfate, tartrate, teoclate, and tosylate. 3. The compound of any preceding claim, wherein X- is selected from the group consisting of Cl-, Br-, I-, and MeSO 3 -. 4. The compound of any one of claims 1-3, wherein R 5 is CF 3 . 5. The compound of claim 1, having a structure selected from the group consisting of: , 7. The compound of 8. The compound of claim 1, wherein R 5 is CF 3 at each occurrence. 9. The compound of claim 1, wherein R 5 is H at each occurrence. 10. A pharmaceutical composition comprising the compound of any one of claims 1-9, and a pharmaceutically acceptable carrier 11. The pharmaceutical composition of claim 10, wherein the carrier is selected from the group consisting of a sugar, lactose, glucose, sucrose, a starch, corn starch, potato starch, cellulose, sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, tragacanth, malt, gelatin, talc, cocoa butter, a glycol, propylene glycol, a polyols, glycerin, sorbitol, mannitol, polyethylene glycol, an ester, ethyl oleate, ethyl laurate, agar, a buffering agent, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer’s solution, ethyl alcohol, a phosphate buffer solution. 12. The pharmaceutical composition of claim 10, wherein the excipient is selected from the group consisting of lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, cyclodextrins, crystalline cellulose, silicic acid. 13. A method for treating or preventing tumor recurrence and/or metastasis, the method comprising administering to a patient at risk of tumor recurrence and/or metastasis a pharmaceutically effective amount of a pharmaceutical composition comprising the compound of any one of claims 1-9. 14. The method of claim 13, wherein the administering is performed at least one of prior to a cancer treatment, with a cancer treatment, and following a cancer treatment. 15. A method for inhibiting the propagation of cancer stem cells in a patient, the method comprising administering to the patient a pharmaceutically effective amount of a pharmaceutical composition comprising the compound of any one of claims 1-9. 16. The method of claim 15, wherein the administering is performed at least one of prior to a cancer treatment, with a cancer treatment, and following a cancer treatment. 17. A method for treating cancer, the method comprising: administering to a person having cancer a pharmaceutically effective amount of a pharmaceutical composition comprising the compound of any one of claims 1-9. 18. The method of claim 17, wherein the administering is performed at least one of prior to a cancer treatment, with a cancer treatment, and following a cancer treatment.

Description

MITOCHONDRIA SPECIFIC TRANSCRIPTION INHIBITOR COMPOUNDS FIELD [0001] The present disclosure relates to mitochondria specific transcription inhibitors, or MSTI compounds, that inhibit the propagation of cancer stem cells (CSCs) and senescent cells through selectively inhibiting CSC mitochondrial transcription. BACKGROUND [0002] The biological process of aging continues to receive significant attention in the scientific and medical research communities. Physiologic aging relates, at least in part, to an increase in the rate of oxidative damage to cellular components, including DNA, lipids, proteins, and the like. The increased oxidative damage creates an imbalance that disrupts self-regulating processes at the cellular level. Further, aging correlates to an accumulation of lipofuscin in neuron cytoplasm. Modern research also indicates that aging is a consequence of naturally occurring DNA damage, resulting in abnormal DNA alterations, accumulating over time. Both mitochondrial and nuclear DNA damage can contribute to aging, indirectly through increasing apoptosis and cellular senescence, and directly by increasing cell dysfunction. Accumulated DNA damage can lead to loss of cells and, in surviving cells, loss of gene expression and mutation – effects that, in infrequently dividing cells, produce indicia of aging. Cellular senescence results when aged cells cease cellular division, believed to occur following various environmental damaging events, abnormal cell growth, autophagy, and oxidative stress, among other factors. Senescence Associated Secretory Phenotype (“SASP”) is a characteristic of senescent cells, and lead to a proteotoxic impairment of healthy cell function, including inflammatory or anti-inflammatory and tumor or anti-tumor effects, depending on a host of factors. The impact of SASP-related chronic inflammation impacts the immune system’s normal ability to remove senescent cells, and cells providing an immune function can be conscripted by SASP into senescent cells. Biomarkers of cellular senescence have been found to accumulate as mammals age, and contribute to a wide range of age-related diseases, including Alzheimer’s, lateral sclerosis, and type 2 diabetes. And with respect to frequently dividing cells, accumulated DNA damage can become a prominent cause of cancer. [0003] Aging thus increases the likelihood of developing cancer, and researchers have struggled to develop new anti-cancer and anti-aging or senolytic treatments. Conventional cancer therapies (e.g., irradiation, alkylating agents such as cyclophosphamide, and anti-metabolites such as 5-Fluorouracil) have attempted to selectively detect and eradicate fast-growing cancer cells by interfering with cellular mechanisms involved in cell growth and DNA replication. Other cancer therapies have used immunotherapies that selectively bind mutant tumor antigens on fast-growing cancer cells (e.g., monoclonal antibodies). Unfortunately, tumors often recur following these therapies at the same or different site(s), indicating that not all cancer cells have been eradicated. Cancer stem cells, in particular, survive for various reasons, and lead to treatment failure. Relapse may be due to insufficient chemotherapeutic dosage and/or emergence of cancer clones resistant to therapy. Hence, novel cancer treatment strategies are needed to overcome the deficiencies of conventional therapies. [0004] Advances in mutational analysis have allowed in-depth study of the genetic mutations that occur during cancer development. Despite having knowledge of the genomic landscape, modern oncology has had difficulty with identifying primary driver mutations across cancer subtypes. The harsh reality appears to be that each patient’s tumor is unique, and a single tumor may contain multiple divergent clone cells. What is needed, then, is a new approach that emphasizes commonalities between different cancer types. Targeting the metabolic differences between tumor and normal cells holds promise as a novel cancer treatment strategy. An analysis of transcriptional profiling data from human breast cancer samples revealed more than 95 elevated mRNA transcripts associated with mitochondrial biogenesis and/or mitochondrial translation. Sotgia et al., Cell Cycle, 11(23):4390-4401 (2012). Additionally, more than 35 of the 95 upregulated mRNAs encode mitochondrial ribosomal proteins (MRPs). Proteomic analysis of human breast cancer stem cells likewise revealed the significant overexpression of several mitoribosomal proteins as well as other proteins associated with mitochondrial biogenesis. Lamb et al., Oncotarget, 5(22):11029-11037 (2014). [0005] Cancer cell mitochondrial metabolism has been the target of recent explorative research, with respect to both searching for anti-cancer therapeutic targets and senolytic therapeutic targets. Mitochondria are extremely dynamic organelles in constant division, elongation and connection to each other to form tubular networks or fragm