New publications supporting the efficacy of ACU-D2 & d3



March 11, 2021Peachtree Corners, GA: Accuitis gained further validation of the therapeutic potential of its preclinical compounds ACU-D2 & ACU-D3 . Our first in class therapeutic candidates now have completed in-vivo and in vitro studies validating the therapeutic potential and mechanism of action in high value and underserved disease states such as Systemic Sclerosis (ACU-D2) BRAF Mutated and vemurafenib-resistant Melanoma, and selective TRAP1 inhibitor that can be used to better dissect TRAP1 biochemical functions and to tailor novel tumor-targeting strategies in rade diseases such as neurofibromatosis (ACU-D3)
About Accuitis, Inc. Accuitis, Inc., headquartered in Peachtree Corners GA, is a clinical-stage biopharmaceutical company developing multiple first-in-class drug therapies to treat chronic, diseases. Visit www.accuitis.com for more information.
Contacts: Accuitis, Inc.
Rick Coulon
Chief Executive Officer
info@accuitis.com



ACU-D3
Honokiol Bis-Dichloroacetate Is a Selective Allosteric Inhibitor of the Mitochondrial Chaperone TRAP1



Sanchez-Martin C, Menon D, Moroni E, Ferraro M, Masgras I, Elsey J, Arbiser JL, Colombo G, Rasola Honokiol Bis-Dichloroacetate Is a Selective Allosteric Inhibitor of the Mitochondrial Chaperone TRAP1A. Antioxid Redox Signal. 2021 Mar 134(7):505-516. doi: 10.1089/ars.2019.7972. Epub 2020 Jun 23. PMID: 32438819.
Abstract Aims:TNF receptor-associated protein 1 (TRAP1), the mitochondrial paralog of the heat shock protein 90 (Hsp90) family of molecular chaperones, is required for neoplastic growth in several tumor cell models, where it inhibits succinate dehydrogenase (SDH) activity, thus favoring bioenergetic rewiring, maintenance of redox homeostasis, and orchestration of a hypoxia-inducible factor 1-alpha (HIF1α)-mediated pseudohypoxic program.
Development of selective TRAP1 inhibitors is instrumental for targeted development of antineoplastic drugs, but it has been hampered up to now by the high degree of homology among catalytic pockets of Hsp90 family members. The vegetal derivative honokiol and its lipophilic bis-dichloroacetate ester, honokiol DCA (HDCA), are small-molecule compounds with antineoplastic activity. HDCA leads to oxidative stress and apoptosis in in vivo tumor models and displays an action that is functionally opposed to that of TRAP1, as it induces both SDH and the mitochondrial deacetylase sirtuin-3 (SIRT3), which further enhances SDH activity.
We investigated whether HDCA could interact with TRAP1, inhibiting its chaperone function, and the effects of HDCA on tumor cells harboring TRAP1. Results: An allosteric binding site in TRAP1 is able to host HDCA, which inhibits TRAP1 but not Hsp90 ATPase activity. In neoplastic cells, HDCA reverts TRAP1-dependent downregulation of SDH, decreases proliferation rate, increases mitochondrial superoxide levels, and abolishes tumorigenic growth. Innovation: HDCA is a potential lead compound for the generation of antineoplastic approaches based on the allosteric inhibition of TRAP1 chaperone activity.
Conclusions: We have identified a selective TRAP1 inhibitor that can be used to better dissect TRAP1 biochemical functions and to tailor novel tumor-targeting strategies. Keywords: TRAP1 antineoplastic compound honokiol mitochondria molecular dynamics neurofibromatosis type 1.

https://pubmed.ncbi.nlm.nih.gov/32438819/


ACU-D3
Therapeutic Potential N VEMURAFENIB-RESISTANT MELANOMA: Honokiol bis-dichloroacetate (Honokiol DCA) demonstrates activity in vemurafenib-resistant melanoma in vivo



Bonner MY, Karlsson I, Rodolfo M, Arnold RS, Vergani E, Arbiser JL. Honokiol bis-dichloroacetate (Honokiol DCA) demonstrates activity in vemurafenib-resistant melanoma in vivo. Oncotarget. 2016 Mar 157(11):12857-68. doi: 10.18632/oncotarget.7289. PMID: 26871475 PMCID: PMC4914326.
ABSTRACTThe majority of human melanomas bears BRAF mutations and thus is treated with inhibitors of BRAF, such as vemurafenib. While patients with BRAF mutations often demonstrate an initial dramatic response to vemurafenib, relapse is extremely common. Thus, novel agents are needed for the treatment of these aggressive melanomas.
Honokiol is a small molecule compound derived from Magnolia grandiflora that has activity against solid tumors and hematopoietic neoplasms. In order to increase the lipophilicity of honokiol, we have synthesized honokiol DCA, the dichloroacetate ester of honokiol. In addition, we synthesized a novel fluorinated honokiol analog, bis-trifluoromethyl-bis-(4-hydroxy-3-allylphenyl) methane (hexafluoro). Both compounds exhibited activity against A375 melanoma in vivo, but honokiol DCA was more active.
Gene arrays comparing treated with vehicle control tumors demonstrated induction of the respiratory enzyme succinate dehydrogenase B (SDHB) by treatment, suggesting that our honokiol analogs induce respiration in vivo. We then examined its effect against a pair of melanomas, LM36 and LM36R, in which LM36R differs from LM36 in that LM36R has acquired vemurafenib resistance. Honokiol DCA demonstrated in vivo activity against LM36R (vemurafenib resistant) but not against parental LM36.
Honokiol DCA and hexafluoro inhibited the phosphorylation of DRP1, thus stimulating a phenotype suggestive of respiration through mitochondrial normalization. Honokiol DCA may act in vemurafenib resistant melanomas to increase both respiration and reactive oxygen generation, leading to activity against aggressive melanoma in vivo.
https://pubmed.ncbi.nlm.nih.gov/26871475/


ACU-D2:
Therapeutic Potential for the treatment of Systemic Scleroderma SIRT3 is attenuated in systemic sclerosis skin and lungs, and its pharmacologic activation mitigates organ fibrosis



Akamata K, Wei J, Bhattacharyya M, Cheresh P, Bonner MY, Arbiser JL, Raparia K, Gupta MP, Kamp DW, Varga J. SIRT3 is attenuated in systemic sclerosis skin and lungs, and its pharmacologic activation mitigates organ fibrosis. Oncotarget. 2016 Oct 257(43):69321-69336. doi: 10.18632/oncotarget.12504. PMID: 27732568 PMCID: PMC5342480.
AbstractConstitutive fibroblast activation is responsible for organ fibrosis in fibrotic disorders including systemic sclerosis (SSc), but the underlying mechanisms are not fully understood, and effective therapies are lacking. We investigated the expression of the mitochondrial deacetylase sirtuin 3 (SIRT3) and its modulation by hexafluoro, a novel fluorinated synthetic honokiol analogue, in the context of fibrosis. We find that augmenting cellular SIRT3 by forced expression in normal lung and skin fibroblasts, or by hexafluoro treatment, blocked intracellular TGF-ß signaling and fibrotic responses, and mitigated the activated phenotype of SSc fibroblasts. Moreover, hexafluoro attenuated mitochondrial and cytosolic reactive oxygen species (ROS) accumulation in TGF-β-treated fibroblasts. Remarkably, we found that the expression of SIRT3 was significantly reduced in SSc skin biopsies and explanted fibroblasts, and was suppressed by TGF-β treatment in normal fibroblasts. Moreover, tissue levels of acetylated MnSOD, a sensitive marker of reduced SIRT3 activity, were dramatically enhanced in lesional skin and lung biopsies from SSc patients. Mice treated with hexafluoro showed substantial attenuation of bleomycin-induced fibrosis in the lung and skin. Our findings reveal a cell-autonomous function for SIRT3 in modulating fibrotic responses, and demonstrate the ability of a novel pharmacological SIRT3 agonist to attenuate fibrosis in vitro and in vivo. In light of the impaired expression and activity of SIRT3 associated with organ fibrosis in SSc, pharmacological approaches for augmenting SIRT3 might have therapeutic potential. Keywords: Pathology Section ROS SIRT3 TGF-β fibrosis myofibroblast.
https://pubmed.ncbi.nlm.nih.gov/27732568/



NOVEMBER 23, 2015 07:45 AM EASTERN STANDARD TIME



Accuitis, Inc. completes latest financing round and elects Geoffrey Meacham PhD to Board of Directors



Cumming, Ga. (Business Wire) Accuitis, Inc. today announced the closing of a $1 million Preferred financing round. The financing was a private placement with a significant investment from the recently formed Atlanta based, Bio/Med Investor Network. The Georgia Research Alliance, through its GRA Ventures program, has also granted a Phase IIIA loan. Accuitis expects to use proceeds from this financing to fund continued development of Accuitis’s first in class topical proteasome inhibitor (ACU-D1) for the treatment of Rosacea into Phase 1-2 clinical trials in 2016.

Accuitis has also elected Geoff Meacham, PhD to the Board of Directors. Dr. Meacham is managing director and senior research analyst covering the biopharmaceutical industry at Barclays. Previously, Meacham was with J.P.Morgan as a senior biotechnology analyst, and was an equity analyst at UBS, following early-stage biotech and life science companies. He has also worked in the pharmaceutical industry in a research-and-development capacity, Meacham holds a PhD in molecular cell biology from UAB and a bachelor’s degree in biology/microbiology from the University of Georgia.

About Accuitis, Inc.

Accuitis, Inc., headquartered in Cumming, GA, is a pre- clinical-stage biopharmaceutical company developing first-in-class drug therapies to treat chronic, diseases of the skin and eye. Accuitis lead product is a topical proteasome inhibitor discovered at Emory University and is focused on treating Rosacea a dermato-ophthalmic condition which effects over 43 million people in the US & Western Europe, and other inflammatory skin diseases. A start-up out of the Emory Univerity tech transfer office, Accuitis is a GRA Ventures portfolio company and has received significant support from the Georgia Research Alliance. Visit www.accuitis.com for more information.


About Bio/Med Investor Network

The Bio/Med Investor Network was formed in 2014 to address the need for funding in early-stage bioscience and healthcare companies. Network members are accredited angel investors specializing in these fields to provide a high level of scrutiny and guidance for growing companies. The Network is based in Atlanta, Georgia with about 40 investor/members. More information can be found at www.biomedinvestors.com.

About the Georgia Research Alliance:

The Georgia Research Alliance (GRA) works to expand research and commercialization capacity in Georgia’s universities to recruit world-class talent, seed new companies and transform lives. For twenty-five years, GRA has worked to strengthen the research enterprise in Georgia by working in partnership with the University System of Georgia and the Georgia Department of Economic Development to create the companies and jobs of Georgia’s future. Visit www.gra.org for more information.



Contacts:

Accuitis, Inc.

Rick Coulon, Chief Executive Officer

info@accuitis.com





November 3, 2014



Psoriasis Pre-Clinical Proof of Concept Study Poster Presented at the American Association of Pharmaceutical Scientists meeting



The results of a pre-clinical study collobaration between Mercer University, Emory University, and Accuitis, Inc. demonstrated our compound significantly reduced IL-6 levels in psoriatic skin vs. a non-treated group, was a non-irritant, and may be a feasible therapy for the treatment of psoriasis



September 28, 2014



US Patent issued for ACU-D1



Accuitis has received notification of the issuance from the USPTO of its patent for the Methods and Compositions for inhibiting proteasome activity via toopical of systemic use.


In addition to the recently issued US patient the company has issued patents in China, Hong Kong, Australia, and Canada. For information contact info@accuitis.com



October 21, 2013



US Patent issued for ACU-D1



Accuitis, Inc. has been chosen to present at the Southeast BIO Investor & Partnering Forum featuring companies with Innovative drug therapies, advanced medical devices, diagnostics and other cutting-edge healthcare technologies from throughout the Southeast will be showcased November 6-7, during the 2013 Southeast BIO Investor & Partnering Forum at the Jefferson Hotel in Richmond, Virginia.

Entrepreneurs representing 22 of the most promising bioscience and medical technology companies in the region will solicit advice and seek investment during the annual life science convention sponsored by Southeast BIO (SEBIO), the regional nonprofit organization dedicated to fostering the growth of the Southeast's life sciences industry. The companies were picked by a selection committee of regional and national venture capitalists.

The MAIN/Stage presenting companies have generally completed at least one round of institutional financing and will have the opportunity to make a 10-minute pitch to the full conference audience on the afternoon of November 6.

Companies chosen for the EARLY/Stage event are seeking their first rounds of investment. They will participate in an individual private advisory session led by early-stage investors, entrepreneurs and experienced life science managers and service providers. Four EARLY/Stage companies will be selected to present to the full conference audience, with an overall "winner" announced at the closing lunch.



November 2, 2012



Accuitis Wins SE Bio investor forum plan competition



Accuitis, Inc. was announced the winner of the SE Bio Plan competition at the SE BIO Investor conference held at the Breakers Hotel in Palm Beach, Florida. The company was chosen as a competition finalist and presenter at the SE BIO Investor Conference, based on the quality of its business plan. A panel of judges from the investor community judged and scored the presentations. These scores will be added to the earlier respective written plan scores to determine the overall winner of the BIO/Plan Competition.





Accuitis, Inc.