PIPELINE — Collaborations Pharmaceuticals, Inc.

Our Pipeline

Our work using machine learning for bacteria, viruses, parasites and rare diseases has demonstrated that we can identify molecules with potential in vivo activity that can lead to NIH funding to build our pipeline of drug candidates.

Category	Development Status

DISEASE / TARGET(S)	PRECLINICAL IN-VITRO	PRECLINICAL IN-VIVO	PRE-IND	CLINICAL	RARE DISEASE DESIGNATION	ORPHAN DESIGNATION	NIH / DOD FUNDING	MACHINE LEARNING	PATENT FILING
VIRUSES

Ebola We have identified 3 molecules (pyronaridine, tilorone and quinacrine) with in vitro activity against three strains of Ebola virus. These three molecules were also active in vivo in a mouse adapted virus model. One molecule Pyronaridine, has to date, shown activity in a guinea pig adapted virus model and is ready to go into a non-human primate model. We have 3 orphan drug designations for this disease. Ekins S, Freundlich JS, Clark AM, Anantpadma M, Davey RA, Madrid P.Machine learning models identify molecules active against the Ebola virus in vitro. F1000Res. 2015 Oct 20;4:1091. doi: 10.12688/f1000research.7217.3. eCollection 2015.PMID: 26834994 Ekins S, Lingerfelt MA, Comer JE, Freiberg AN, Mirsalis JC, O'Loughlin K, Harutyunyan A, McFarlane C, Green CE, Madrid PB. Efficacy of Tilorone Dihydrochloride against Ebola Virus Infection. Antimicrob Agents Chemother. 2018 Jan 25;62(2):e01711-17. doi: 10.1128/AAC.01711-17. Print 2018 Feb.PMID: 29133569 Lane TR, Comer JE, Freiberg AN, Madrid PB, Ekins S. Repurposing Quinacrine against Ebola Virus Infection In Vivo.Antimicrob Agents Chemother. 2019 Aug 23;63(9):e01142-19. doi: 10.1128/AAC.01142-19. Print 2019 Sep.PMID: 31307979 Lane TR, Massey C, Comer JE, Anantpadma M, Freundlich JS, Davey RA, Madrid PB, Ekins S. Repurposing the antimalarial pyronaridine tetraphosphate to protect against Ebola virus infection.PLoS Negl Trop Dis. 2019 Nov 21;13(11):e0007890. doi: 10.1371/journal.pntd.0007890. eCollection 2019 Nov.PMID: 31751347 Lane TR, Massey C, Comer JE, Freiberg AN, Zhou H, Dyall J, Holbrook MR, Anantpadma M, Davey RA, Madrid PB, Ekins S. Pyronaridine tetraphosphate efficacy against Ebola virus infection in guinea pig. Antiviral Res. 2020 Sep;181:104863. doi: 10.1016/j.antiviral.2020.104863. Epub 2020 Jul 16.PMID: 32682926 Lane TR, Dyall J, Mercer L, Goodin C, Foil DH, Zhou H, Postnikova E, Liang JY, Holbrook MR, Madrid PB, Ekins S. Repurposing Pyramax®, quinacrine and tilorone as treatments for Ebola virus disease. Antiviral Res. 2020 Oct;182:104908. doi: 10.1016/j.antiviral.2020.104908. Epub 2020 Aug 13.PMID: 32798602

HIV We have developed a novel next generation pM NNRTI for HIV that does not show CNS toxicity and maintains activity across different mutations. This work has been featured on Russian TV https://www.youtube.com/watch?app=desktop&v=XI7iahzIVik Lane T, Makarov V, Nelson JAE, Meeker RB, Sanna G, Riabova O, Kazakova E, Monakhova N, Tsedilin A, Urbina F, Jones T, Suchy A, Ekins S. N-Phenyl-1-(phenylsulfonyl)-1H-1,2,4-triazol-3-amine as a New Class of HIV-1 Non-nucleoside Reverse Transcriptase Inhibitor. J Med Chem. 2023 May 11;66(9):6193-6217. doi: 10.1021/acs.jmedchem.2c02055. Epub 2023 May 2.PMID: 37130343

Enteroviruses An analog of a clinical stage compound pleconaril, with potent activity across these enteroviruses in vitro was identified. We have demonstrated EV68, EV71, Polio, CVB3, CVB5 and Echovirus activities. We have also generated in vivo data for EV68 and CVB5. Our lead candidate is 10x more potent than pleconaril vs EV68 in vitro with no apparent CYP3A4 induction. This compound has demonstrated in vivo efficacy in a 5 day mouse model provided by NIAID. Recent studies by several research groups have demonstrated enterovirus infection in the pancreas of newly diagnosed type I diabetes (T1D) patients and therefore a strong association with this disease. A clinical trial recently showed that pleconaril and ribavirin can significantly increase serum C-peptide versus placebo, suggesting the potential to preserve insulin production in patients with T1D. Our lead candidate may have applications for T1D and other diseases. Lane TR, Fu J, Sherry B, Tarbet B, Hurst BL, Riabova O, Kazakova E, Egorova A, Clarke P, Leser JS, Frost J, Rudy M, Tyler KL, Klose T, Volobueva AS, Belyaevskaya SV, Zarubaev VV, Kuhn RJ, Makarov V, Ekins S. Efficacy of an isoxazole-3-carboxamide analog of pleconaril in mouse models of Enterovirus-D68 and Coxsackie B5. Antiviral Res. 2023 Aug;216:105654 Volobueva A, Egorova A, Galochkina A, Ekins S, Zarubaev V, Makarov V. The Evolution of Pleconaril: Modified O-Alkyl Linker Analogs Have Biological Activity towards Coxsackievirus B3 Nancy. Molecules. 2020 Mar 16;25(6):1345 Egorova A, Kazakova E, Jahn B, Ekins S, Makarov V, Schmidtke M. Novel pleconaril derivatives: Influence of substituents in the isoxazole and phenyl rings on the antiviral activity against enteroviruses. Eur J Med Chem. 2020 Feb 15;188:112007 Egorova A, Ekins S, Schmidtke M, Makarov V. Back to the future: Advances in development of broad-spectrum capsid-binding inhibitors of enteroviruses. Eur J Med Chem. 2019 Sep 15;178:606-622

Covid-19 We have leveraged multiple collaborators to pursue small molecule inhibitors. We identified pyronaridine, quinacrine, tilorone and vandetanib as well as many other compounds as active in vitro. Pyronaridine demonstrated efficacy in a mouse model and vandetanib demonstrated activity against the cytokine storm in vitro and in vivo. Puhl AC, Fritch EJ, Lane TR, Tse LV, Yount BL, Sacramento CQ, Fintelman-Rodrigues N, Tavella TA, Maranhão Costa FT, Weston S, Logue J, Frieman M, Premkumar L, Pearce KH, Hurst BL, Andrade CH, Levi JA, Johnson NJ, Kisthardt SC, Scholle F, Souza TML, Moorman NJ, Baric RS, Madrid PB, Ekins S. Repurposing the Ebola and Marburg Virus Inhibitors Tilorone, Quinacrine, and Pyronaridine: In Vitro Activity against SARS-CoV-2 and Potential Mechanisms. ACS Omega. 2021 Mar 10;6(11):7454-7468. doi: 10.1021/acsomega.0c05996. eCollection 2021 Mar 23.PMID: 33778258 Puhl AC, Gomes GF, Damasceno S, Godoy AS, Noske GD, Nakamura AM, Gawriljuk VO, Fernandes RS, Monakhova N, Riabova O, Lane TR, Makarov V, Veras FP, Batah SS, Fabro AT, Oliva G, Cunha FQ, Alves-Filho JC, Cunha TM, Ekins S. Pyronaridine Protects against SARS-CoV-2 Infection in Mouse.ACS Infect Dis. 2022 Jun 10;8(6):1147-1160. doi: 10.1021/acsinfecdis.2c00091. Epub 2022 May 24.PMID: 35609344 Puhl AC, Gomes GF, Damasceno S, Fritch EJ, Levi JA, Johnson NJ, Scholle F, Premkumar L, Hurst BL, Lee-Montiel F, Veras FP, Batah SS, Fabro AT, Moorman NJ, Yount BL, Dickmander RJ, Baric RS, Pearce KH, Cunha FQ, Alves-Filho JC, Cunha TM, Ekins S. Vandetanib Blocks the Cytokine Storm in SARS-CoV-2-Infected Mice.ACS Omega. 2022 Aug 29;7(36):31935-31944. doi: 10.1021/acsomega.2c02794. eCollection 2022 Sep 13.PMID: 36097511 Vignaux PA, Lane TR, Puhl AC, Hau RK, Wright SH, Cherrington NJ, Ekins S. Transporter Inhibition Profile for the Antivirals Tilorone, Quinacrine and Pyronaridine.ACS Omega. 2023 Mar 24;8(13):12532-12537. doi: 10.1021/acsomega.3c00724. eCollection 2023 Apr 4.PMID: 37033868

Hepatitis B With collaborators at SLU we have identified a novel molecule series with in vitro activity (novel target/mechanism) and this has been verified by testing using NIAID resources. Jones T, Tavis JE, Li Q, Riabova O, Monakhova N, Bradley DP, Lane TR, Makarov V, Ekins S. Antiviral Evaluation of Dispirotripiperazines against Hepatitis B Virus. J Med Chem. 2023 Sep 14;66(17):12459-12467

Nipah Virus We have identified a nM inhibitor of nipah virus in various cell types. There is concern that Nipah could cause the next pandemic: https://www.bbc.com/future/article/20210106-nipah-virus-how-bats-could-cause-the-next-pandemic.

Yellow Fever We have identified several novel inhibitor series for this virus. Kazakova E, Lane TR, Jones T, Puhl AC, Riabova O, Makarov V, Ekins S. 1-Sulfonyl-3-amino-1H-1,2,4-triazoles as Yellow Fever Virus Inhibitors: Synthesis and Structure-Activity Relationship. ACS Omega. 2023 Nov 1;8(45):42951-42965 Gawriljuk VO, Foil DH, Puhl AC, Zorn KM, Lane TR, Riabova O, Makarov V, Godoy AS, Oliva G, Ekins S. Development of Machine Learning Models and the Discovery of a New Antiviral Compound against Yellow Fever Virus.J Chem Inf Model. 2021 Aug 23;61(8):3804-3813. doi: 10.1021/acs.jcim.1c00460. Epub 2021 Jul 21.PMID: 34286575 Puhl AC, Fernandes RS, Godoy AS, Gil LHVG, Oliva G, Ekins S. The protein disulfide isomerase inhibitor 3-methyltoxoflavin inhibits Chikungunya virus.Bioorg Med Chem. 2023 Apr 1;83:117239. doi: 10.1016/j.bmc.2023.117239. Epub 2023 Mar 15.PMID: 36940609

Chickungunya Virus We have identified a novel inhibitor for this virus. Puhl AC, Fernandes RS, Godoy AS, Gil LHVG, Oliva G, Ekins S. The protein disulfide isomerase inhibitor 3-methyltoxoflavin inhibits Chikungunya virus.Bioorg Med Chem. 2023 Apr 1;83:117239. doi: 10.1016/j.bmc.2023.117239. Epub 2023 Mar 15.PMID: 36940609

Marburg Virus We have identified 3 molecules (pyronaridine, tilorone and quinacrine) with in vitro activity against two strains of Marburg virus. Lane TR, Massey C, Comer JE, Freiberg AN, Zhou H, Dyall J, Holbrook MR, Anantpadma M, Davey RA, Madrid PB, Ekins S. Pyronaridine tetraphosphate efficacy against Ebola virus infection in guinea pig. Antiviral Res. 2020 Sep;181:104863. doi: 10.1016/j.antiviral.2020.104863. Epub 2020 Jul 16.PMID: 32682926

H1N1 Influenza We have multiple lead series being evaluated in vitro.
BACTERIA / PARASITES

Malaria We are pursuing pyronaridine as a single agent treatment based on already completed clinical studies performed by others. We have an orphan drug designation and rare pediatric disease designation for this disease. We have also developed novel pyronaridine analogs with comparable activity across Plasmodium falciparum and drug resistant strains with collaborators.

Chagas Disease With collaborators at UCSD, we have identified pyronaridine as demonstrating activity against T cruzi in vitro and in vivo in mice. We have two orphan drug designations for this disease. Ekins S, de Siqueira-Neto JL, McCall LI, Sarker M, Yadav M, Ponder EL, Kallel EA, Kellar D, Chen S, Arkin M, Bunin BA, McKerrow JH, Talcott C. Machine Learning Models and Pathway Genome Data Base for Trypanosoma cruzi Drug Discovery.PLoS Negl Trop Dis. 2015 Jun 26;9(6):e0003878. doi: 10.1371/journal.pntd.0003878. eCollection 2015.PMID: 26114876

Staphlococcus Aureus With collaborations at SLU we have identified several small molecule inhibitors, with studies ongoing.

Cryptococcus Neoformans With collaborators at SLU we have identified several novel small molecule inhibitors in vitro. Donlin MJ, Lane TR, Riabova O, Lepioshkin A, Xu E, Lin J, Makarov V, Ekins S. Discovery of 5-Nitro-6-thiocyanatopyrimidines as Inhibitors of Cryptococcus neoformans and Cryptococcus gattii. ACS Med Chem Lett. 2021 Apr 7;12(5):774-781. doi: 10.1021/acsmedchemlett.1c00038. PMID: 34055225

Mycobacterium Tuberculosis We have developed multiple compounds showing in vitro activity with collaborators. Our most advanced candidate is a third generation DprE1 inhibitor with potent in vitro and in vivo efficacy. We are keen to pursue this as a novel, long acting agent. A second compound with promising in vitro activity is currently being evaluated. Lane TR, Urbina F, Rank L, Gerlach J, Riabova O, Lepioshkin A, Kazakova E, Vocat A, Tkachenko V, Cole S, Makarov V, Ekins S. Machine Learning Models for Mycobacterium tuberculosisIn Vitro Activity: Prediction and Target Visualization. Mol Pharm. 2022 Feb 7;19(2):674-689. doi: 10.1021/acs.molpharmaceut.1c00791. Epub 2021 Dec 29.PMID: 34964633

Mycobacterium Absceccus To date we have identified novel low uM compounds. Schmalstig AA, Zorn KM, Murcia S, Robinson A, Savina S, Komarova E, Makarov V, Braunstein M, Ekins S. Mycobacterium abscessus drug discovery using machine learning.Tuberculosis (Edinb). 2022 Jan;132:102168. doi: 10.1016/j.tube.2022.102168. Epub 2022 Jan 20.PMID: 35077930

Neisseria Gonorrhoeae We have identified novel inhibitors in vitro with an academic collaborator and are in the process of target identification.
RARE DISEASES

Batten Disease (CLN1) Batten Disease is a genetic disease caused by an autosomal recessive mutation. The infantile onset form termed CLN1 disease is characterized by progressive intellectual and motor deterioration, seizures, loss of vision, and early death. There is currently no treatment for CLN1. We are developing a recombinant human enzyme replacement therapy for CLN1. A recent paper from our collaborators described the efficacy of this protein in mice and sheep. We are currently manufacturing the protein in preparation for IND enabling toxicity testing. This protein will be delivered ICV. We have had our preIND meeting with the FDA (May 2023). We have an orphan drug designation and rare pediatric disease designation for this treatment for this disease. We have also identified several novel small molecules as potential chaperones being tested in vitro. If you are a CLN1 family and want to hear more about what we are doing please contact us. You can also learn more in our recent presentation below.These foundations also have useful information: https://bdsra.org/ https://taylorstale.org/ https://haleysheroesfoundation.org https://beyondbatten.org http://www.bdfa-uk.org.uk Kazakova E, Lane TR, Jones T, Puhl AC, Riabova O, Makarov V, Ekins S. 1-Sulfonyl-3-amino-1H-1,2,4-triazoles as Yellow Fever Virus Inhibitors: Synthesis and Structure-Activity Relationship. ACS Omega. 2023 Nov 1;8(45):42951-42965 Gawriljuk VO, Foil DH, Puhl AC, Zorn KM, Lane TR, Riabova O, Makarov V, Godoy AS, Oliva G, Ekins S. Development of Machine Learning Models and the Discovery of a New Antiviral Compound against Yellow Fever Virus.J Chem Inf Model. 2021 Aug 23;61(8):3804-3813. doi: 10.1021/acs.jcim.1c00460. Epub 2021 Jul 21.PMID: 34286575 Puhl AC, Fernandes RS, Godoy AS, Gil LHVG, Oliva G, Ekins S. The protein disulfide isomerase inhibitor 3-methyltoxoflavin inhibits Chikungunya virus.Bioorg Med Chem. 2023 Apr 1;83:117239. doi: 10.1016/j.bmc.2023.117239. Epub 2023 Mar 15.PMID: 36940609

Batten Disease (CLN1) Batten Disease is a genetic disease caused by an autosomal recessive mutation. The infantile onset form termed CLN1 disease is characterized by progressive intellectual and motor deterioration, seizures, loss of vision, and early death. There is currently no treatment for CLN1. We are developing a recombinant human enzyme replacement therapy for CLN1. A recent paper from our collaborators described the efficacy of this protein in mice and sheep. We are currently manufacturing the protein in preparation for IND enabling toxicity testing. This protein will be delivered ICV. We have had our preIND meeting with the FDA (May 2023). We have an orphan drug designation and rare pediatric disease designation for this treatment for this disease. We have also identified several novel small molecules as potential chaperones being tested in vitro. If you are a CLN1 family and want to hear more about what we are doing please contact us. You can also learn more in our recent presentation below.These foundations also have useful information: https://bdsra.org/ https://taylorstale.org/ https://haleysheroesfoundation.org https://beyondbatten.org http://www.bdfa-uk.org.uk Kazakova E, Lane TR, Jones T, Puhl AC, Riabova O, Makarov V, Ekins S. 1-Sulfonyl-3-amino-1H-1,2,4-triazoles as Yellow Fever Virus Inhibitors: Synthesis and Structure-Activity Relationship. ACS Omega. 2023 Nov 1;8(45):42951-42965 Gawriljuk VO, Foil DH, Puhl AC, Zorn KM, Lane TR, Riabova O, Makarov V, Godoy AS, Oliva G, Ekins S. Development of Machine Learning Models and the Discovery of a New Antiviral Compound against Yellow Fever Virus.J Chem Inf Model. 2021 Aug 23;61(8):3804-3813. doi: 10.1021/acs.jcim.1c00460. Epub 2021 Jul 21.PMID: 34286575 Puhl AC, Fernandes RS, Godoy AS, Gil LHVG, Oliva G, Ekins S. The protein disulfide isomerase inhibitor 3-methyltoxoflavin inhibits Chikungunya virus.Bioorg Med Chem. 2023 Apr 1;83:117239. doi: 10.1016/j.bmc.2023.117239. Epub 2023 Mar 15.PMID: 36940609

Pitt Hopkins Syndrome We have identified a series of calcium channel inhibitors which also inhibit the sodium channel implicated in this rare disease. One of these, nicardipine, demonstrated return of wild type phenotype in the Pitt Hopkins KO mouse. The in vitro and in vivo work has been published and was all funded by the Pitt Hopkins Research Foundation. We have an orphan drug designation and rare pediatric disease designation for this disease. Ekins S, Gerlach J, Zorn KM, Antonio BM, Lin Z, Gerlach A. Repurposing Approved Drugs as Inhibitors of Kv7.1 and Nav1.8 to Treat PittHopkins Syndrome.Pharm Res. 2019 Jul 22;36(9):137. doi: 10.1007/s11095-019-2671-y.PMID: 31332533 Ekins S, Puhl AC, Davidow A.Pharm Res.Repurposing the Dihydropyridine Calcium Channel Inhibitor Nicardipine as a Nav1.8 Inhibitor In Vivo for Pitt Hopkins Syndrome. 2020 Jun 11;37(7):127. doi: 10.1007/s11095-020-02853-5.PMID: 32529312
CANCER

Cancer We have developed a novel series of FLT3 inhibitors with activity against several cell lines when tested at the NCI. These molecules are undergoing in vivo testing against models for glioblastoma. In partnership with the NIH National Cancer Institute (NCI), we have tested over 250 novel small molecules against 60 different cancer cell types to identify lead molecules against 9 different types of cancer. Our small library of compounds represents an unexplored chemical space of potent therapeutics which are under active development as potential new anticancer drugs. Our most potent therapeutic leads display up to 85% growth inhibition against melanoma and CNS cancer cells in vitro. Other compounds in our library inhibit the growth of colon, renal, lung, prostate, breast, and ovarian cancers between 60 and 80%. We hypothesize that these compounds are a novel class of kinase inhibitors, and current work with this library involves discerning the specific biological mode of action. Neuroblastoma We have identified several novel molecules with in vitro activity in neuroblastoma cells. Chordoma Along with collaborators in the UNC Catalyst group we determined that a combination of 2 kinase inhibitors appears to demonstrate synergy in vitro and initial in vivo studies appear promising. Animal studies have been performed by the Chrodoma Foundation. We have also used our machine learning models to identify a kinase inhibitor that appears just as active (nM) as the most potent molecules in clinical trials. We have an orphan drug designation for this disease. Anderson E, Havener TM, Zorn KM, Foil DH, Lane TR, Capuzzi SJ, Morris D, Hickey AJ, Drewry DH, Ekins S. Synergistic drug combinations and machine learning for drug repurposing in chordoma.Sci Rep. 2020 Jul 31;10(1):12982. doi: 10.1038/s41598-020-70026-w.PMID: 32737414 Rank L, Puhl AC, Havener TM, Anderson E, Foil DH, Zorn KM, Monakhova N, Riabova O, Hickey AJ, Makarov V, Ekins S. Multiple approaches to repurposing drugs for neuroblastoma. Bioorg Med Chem. 2022 Nov 1;73:117043. doi: 10.1016/j.bmc.2022.117043. Epub 2022 Oct 4. PMID: 36208544
Neuroblastoma Various
Chordoma Various
VARIOUS

Alzheimers Disease We have identified new nM inhibitors for GSK-3β and Acetylcholinesterase in vitro. We have also identified molecules hitting several targets that would impact Tau phosphorylation. Vignaux PA, Minerali E, Foil DH, Puhl AC, Ekins S. Machine Learning for Discovery of GSK3β Inhibitors.ACS Omega. 2020 Oct 12;5(41):26551-26561. doi: 10.1021/acsomega.0c03302. eCollection 2020 Oct 20.PMID: 33110983 Vignaux PA, Minerali E, Lane TR, Foil DH, Madrid PB, Puhl AC, Ekins S. The Antiviral Drug Tilorone Is a Potent and Selective Inhibitor of Acetylcholinesterase.Chem Res Toxicol. 2021 May 17;34(5):1296-1307. doi: 10.1021/acs.chemrestox.0c00466. Epub 2021 Jan 5.PMID: 33400519

Psychoplastogens We are developing new psychoplastogens for treating opioid use disorder using our generative AI approach. Urbina F, Lowden CT, Culberson JC, Ekins S. MegaSyn: Integrating Generative Molecular Design, Automated Analog Designer, and Synthetic Viability Prediction. ACS Omega. 2022 May 27;7(22):18699-18713. doi: 10.1021/acsomega.2c01404. PMID: 35694522

Countermeasures We are actively pursuing several different approaches as countermeasures for exposure to different chemical agents.

Stroke In collaboration with scientists at the University of Kentucky we have identified a new small molecule inhibitor of CCR3 /CCR4.
Obesity 5HT2C

Our Work

Ebola

We have identified 3 molecules (pyronaridine, tilorone and quinacrine) with in vitro activity against three strains of Ebola virus. These three molecules were also active in vivo in a mouse adapted virus model. One molecule Pyronaridine, has to date, shown activity in a guinea pig adapted virus model and is ready to go into a non-human primate model.

We have 3 orphan drug designations for this disease.

Enteroviruses

An analog of a clinical stage compound pleconaril, with potent activity across these enteroviruses in vitro was identified. We have demonstrated EV68, EV71, Polio, CVB3, CVB5 and Echovirus activities. We have also generated in vivo data for EV68 and CVB5. Our lead candidate is 10x more potent than pleconaril vs EV68 in vitro with no apparent CYP3A4 induction. This compound has demonstrated in vivo efficacy in a 5 day mouse model provided by NIAID.

Recent studies by several research groups have demonstrated enterovirus infection in the pancreas of newly diagnosed type I diabetes (T1D) patients and therefore a strong association with this disease. A clinical trial recently showed that pleconaril and ribavirin can significantly increase serum C-peptide versus placebo, suggesting the potential to preserve insulin production in patients with T1D. Our lead candidate may have applications for T1D and other diseases.

Covid-19

We have leveraged multiple collaborators to pursue small molecule inhibitors. We identified pyronaridine, quinacrine, tilorone and vandetanib as well as many other compounds as active in vitro. Pyronaridine demonstrated efficacy in a mouse model and vandetanib demonstrated activity against the cytokine storm in vitro and in vivo.

Batten Disease (CLN1)

Batten Disease is a genetic disease caused by an autosomal recessive mutation. The infantile onset form termed CLN1 disease is characterized by progressive intellectual and motor deterioration, seizures, loss of vision, and early death. There is currently no treatment for CLN1.

We are developing a recombinant human enzyme replacement therapy for CLN1. A recent paper from our collaborators described the efficacy of this protein in mice and sheep. We are currently manufacturing the protein in preparation for IND enabling toxicity testing. This protein will be delivered ICV. We have had our preIND meeting with the FDA (May 2023).

We have an orphan drug designation and rare pediatric disease designation for this treatment for this disease.

We have also identified several novel small molecules as potential chaperones being tested in vitro.

If you are a CLN1 family and want to hear more about what we are doing please contact us. You can also learn more in our recent presentation below.These foundations also have useful information:

https://bdsra.org/

https://taylorstale.org/

https://haleysheroesfoundation.org

https://beyondbatten.org

http://www.bdfa-uk.org.uk

Cancer

We have developed a novel series of FLT3 inhibitors with activity against several cell lines when tested at the NCI. These molecules are undergoing in vivo testing against models for glioblastoma.

In partnership with the NIH National Cancer Institute (NCI), we have tested over 250 novel small molecules against 60 different cancer cell types to identify lead molecules against 9 different types of cancer. Our small library of compounds represents an unexplored chemical space of potent therapeutics which are under active development as potential new anticancer drugs.

Our most potent therapeutic leads display up to 85% growth inhibition against melanoma and CNS cancer cells in vitro. Other compounds in our library inhibit the growth of colon, renal, lung, prostate, breast, and ovarian cancers between 60 and 80%. We hypothesize that these compounds are a novel class of kinase inhibitors, and current work with this library involves discerning the specific biological mode of action.

Neuroblastoma

We have identified several novel molecules with in vitro activity in neuroblastoma cells.

Chordoma

Along with collaborators in the UNC Catalyst group we determined that a combination of 2 kinase inhibitors appears to demonstrate synergy in vitro and initial in vivo studies appear promising. Animal studies have been performed by the Chrodoma Foundation. We have also used our machine learning models to identify a kinase inhibitor that appears just as active (nM) as the most potent molecules in clinical trials. We have an orphan drug designation for this disease.