bio june 2018 - dana–farber cancer institute · patent no. 5937968 and u.s. patent application...

Dana-Farber Cancer InstituteChemical Biology Program’s Portfolio

BIO June 2018

Non-confidential slide deckJune 2018

Selective, noncovalent and covalent USP7 inhibitors

• DFCI 2304

• Type: Small molecule• Target: USP7• Investigator: Sara Buhrlage, PhD and Kimberly

Stegmaier, MD, PhD• Development stage: advanced lead optimization

ready for in vivo efficacy• Patent status: Patent application (Development of

USP7 Inhibitors, 62/563,375) filed with priority date of October 2, 2017

• Competitive advantage: First-in-class active site inhibitors of USP7, with covalent and non-covalent compound series established.

• Key publication:

Ilaria Lamberto, Xiaoxi Liu, Hyuk-Soo Seo, Nathan J. Schauer, Roxana E. Iacob, Wanyi Hu, Deepika Das, Tatiana Mikhailova, Ellen L. Weisberg, John R. Engen, Kenneth C. Anderson, Dharminder Chauhan, Sirano Dhe-Paganon, Sara J. Buhrlage (2017) “Structure-Guided Development of a Potent and Selective Non-covalent Active-Site Inhibitor of USP7”, Cell Chemical Biology 24, 1490-1500.

Lamberto et al. (2017) Cell Chem. Biol. 24, 1490-1500

USP10 inhibitors induce degradation of oncogenic

FLT3 kinase

• DFCI 2266

• Type: Small molecule• Target: USP10• Investigator: Sara Buhrlage, PhD, James Griffin, MD,

and Ellen Weisberg, PhD• Development stage: lead optimization• Patent status: “Compositions and Methods for

Identification, Assessment, Prevention and Treatment of AML Using USP10 Biomarkers and Modulators”, Filing Date 20-Sep-2016 62/397,100

• Competitive advantage: Identified USP10 as the critical deubiquitinating enzyme required to stabilize mutant FLT3. Targeting USP10 showed efficacy in preclinical models of mutant FLT3-AML, including cell lines, primary patient specimens and mouse models of oncogenic-FLT3-driven disease. Notably, targeting USP10 overcame FLT3 kinase inhibitor resistance models, and did not impact WT FLT3 levels.

• Key publication:Weisberg et al. Inhibition of USP10 induces degradation of oncogenic FLT3. Nature Chemical Biology. 2017; 13(12):1207-1215.

Weisberg et al. Nature Chem. Biol. 2017; 13(12), 41207-1215.

Selective inhibitor validates ERK5 as key regulator of

ESC identity

• DFCI 1708, 1264

• Type: small molecules• Target: ERK5 (also known as MAPK7 and BMK-1) • Investigator: Nathanael Gray, PhD• Development stage: late lead optimization, POC in

in vivo models• Patent status: Pyrimido-diazepinone kinase scaffold

compounds and methods of treating disorders (PCT/US2010/000050); Pyrimido-diazepinonecompounds and methods of treating disorders (PCT/US2014/030760); Uses of diazepane derivatives (PCT/US2015/014120).

• Competitive advantage: first class of Erk5 inhibitors had off-target effect on Brd4, and many biological effects were Brd4-dependent; JGG045 and JWG071 are newly developed Erk5 inhibitors with Erk5 selectivity.

• Key publication:Williams, C. A. C., Fernandez-Alonso, R., Wang, J., Toth, R., Gray, N. S., & Findlay, G. M. (2016). Erk5 Is a Key Regulator of Naive-Primed Transition and Embryonic Stem Cell Identity. Cell Reports, 16(7), 1820–1828.

Williams et al. Cell Reports. 2016; 16(7):1820-1828.

Selective Bruton’sTyrosine Kinase (BTK)

degraders

• DFCI 2247, 2242

• Type: small molecule degrader (PROTAC)• Target: Bruton’s Tyrosine Kinase (BTK)• Investigator: Nathanael Gray, PhD• Development stage: late lead optimization, POC in

in vivo models• Patent status: PCT filed May 2018 “Degradation of

bruton's tyrosine kinase (btk) by conjugation of btkinhibitors with e3 ligase ligand and methods of use” WO/2018/098275/PCT/US2017/063011; “Degradation of bruton's tyrosine kinase (btk) by conjugation of btkinhibitors with e3 ligase ligand and methods of use” WO/2018/098288; PCT/US2017/063027

• Competitive advantage: Lead compound (compound 1) is a highly potent and selective “triple degrader” of BTK, IKZF1, and IKZF3; compound 1 exhibits greater in vivo efficacy than Imbruvica® and Revlimid® in a patient derived xenograft mantle cell lymphoma mouse model (fig. 1C/D); BTK degraders address a major clinical unmet need: Imbruvica® resistance (fig. 1 A/B)

• Key publication:Huang HT, Dobrovolsky D, Paulk J, Yang G, Weisberg EL, Doctor ZM, Buckley DL, Cho JH, Ko E, Jang J, Shi K, Choi HG, Griffin JD, Li Y, Treon SP, Fischer ES, Bradner JE, Tan L, Gray NS. (2017A Chemoproteomic Approach to Query the Degradable Kinome Using a Multi-kinase Degrader. Cell Chemical Biology, 25(1), 88–99.

Figure1.(A) TMD8cellsoverexpressingeitherBTKWT(top)orBTKC481S(bottom)weretreatedfor3dayswithindicatedcompounds.(B) Top.ImmunoblotofTMD8cellstreatedwithindicatedcompoundsfor16hours.Bottom.Immunoblotfrompatient-derivedMCLcellsxenograftedinNSGmiceafter3daytreatmentasin(C).(C) NSGmice(n=5)weregraftedwithpatient-derivedMCLcells.Onceburdenofdiseasereached~2%,treatmentbeganwithindicatedcompounds:vehicle(IP,BID),compound1(IP,QD,50mg/kg),lenalidomide(IP,QD,50mg/kg),ibrutinib(PO,QD,30mg/kg).Miceweretreatedfortwoweeks.4-6hoursafterthelastdose,peripheralbloodwastakenandquantifiedfordisease burdenviaflowcytometry.(D) Survivalstudyofmicein(C).

Selective peptidomimeticinhibitors of MALT1

• DFCI 2052

• Type: covalent small molecule inhibitor• Target: MALT1• Investigator: Nathanael Gray, PhD• Development stage: late lead optimization, POC in

in vivo models• Patent status: PCT filed March 2017 “MALT1

inhibitors and uses thereof” WO/2017/040304/PCT/US2016/049038

• Competitive advantage: Potential first-in-class MALT1 inhibitor for Activated B-cell like Diffuse Large B-cell Lymphoma (ABC-DLBCL), with activity against ibrutinib-resistant CARD11 mutations.; new class of substrate mimetic MALT1 inhibitors based on Z-VRPR-fmk.


Lorena Fontan, David Scott, John Hatcher, Qi Qiao, IlkayUs, Gabriella Casalena, Mariette Bekkers, Ulrike Philippar, Matthew Durant, Spandan Chennamadhavuni, Hao Wu, Nathaniel Gray, Ari Melnick. Substrate-mimetic covalent inhibitor of MALT1 is most effective against CARD11 mutant ABC-DLBCL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-303. doi:10.1158/1538-7445.AM2017-LB-303

BTSA1 activates BAX to overcome resistance to

apoptosis in AML

• DFCI 1530,1296• Type: Small molecule• Target: BAX (apoptosis)• Investigator: Loren Walensky, MD, PhD & Evripidis

Gavathiotis, PhD• Development stage: POC in in vivo mouse models• Patent status: Chemical Modulators of Pro-Apoptotic

BAX and BCL-2 Polypeptides (Pending and Granted, e.g., European Patent No. 2338056 and U.S. Patent Application Publication No. 20160171150, from International Patent Application PCT/US2009/005568, claiming priority from Oct. 10, 2008); Pyrazol-3-ones that Activate Pro-apoptotic BAX (Pending and Granted, e.g., U.S. Patent No. 9,303,024, from International Patent Application PCT/US2012/059799, claiming priority from Oct. 11, 2011).

• Competitive advantage: novel mechanism of action for direct activation of BAX-mediated apoptosis by targeting the trigger site of BAX; small molecule BAX activators synergize with anti-apoptotic inhibitors (e.g. venetoclax)


Reyna et al. Direct Activation of BAX by BTSA1 Overcomes Apoptosis Resistance in Acute Myeloid Leukemia. Cancer Cell. 2017 Oct 9; 32(4):490-505.

Reyna et al. Cancer Cell. 2017 Oct 9; 32(4):490-505.

Small molecule inhibitors of anti-apoptotic MCL-1 • DFCI 1380, 1614

• Type: Small molecule• Target: MCL-1 (apoptosis)• Investigator: Loren Walensky, MD, PhD• Development stage: lead optimization• Patent status: Small Molecules for the Modulation of

MCL-1 and Methods of Modulating Cell Death, Cell Division, Cell Differentiation, and Methods of Treating Disorders (Pending and Granted, e.g., Japanese Patent No. 5937968 and U.S. Patent Application Publication No. 20150315211, from International Patent Application PCT/US2011/023220, claiming priority from Jan. 29, 2010).

• Competitive advantage: MCL-1 inhibitory molecules for targeting apoptosis in cancer; a series of small molecules that target MCL-1, dissociating inhibitory MCL-1 complexes.

• Key publication:Cohen NA, Stewart ML, Gavathiotis E, Tepper JL, Bruekner SR, Koss B, Opferman JT, Walensky LD. A Competitive Stapled Peptide Screen Identifies a Selective Small Molecule that Overcomes MCL-1 Dependent Leukemia Cell Survival. Chem Biol. 2012; 19(9): 1175-86.

Hydrocarbon double-stapling fortifies natural insulinotropic peptides

• DFCI 1472

• Type: Stapled peptide• Target: GLP1 receptor (diabetes)• Investigator: Loren Walensky, MD, PhD• Development stage: late lead optimization• Patent status: Stabilized Insulinotropic Peptides and

Methods of Use (Pending and Granted, e.g., U.S. Patent Nos. 9,296,805 and 9,695,224, from International Patent Application PCT/US2011/043465, claiming priority from June 6, 2009).

• Competitive advantage: a series of differentially stapled and structurally-reinforced insulinotropicpeptides modeled after GLP1; stapled peptides maintain bioactive structure, resists proteolytic degradation in vivo, increased binding potency.


Bird GH, Madani N, Perry AF, Princiotto AM, Supko JG, He X, Gavathiotis E, Sodroski JF, Walensky LD. Hydrocarbon Double-Stapling Remedies the Proteolytic Instability of a Lengthy Peptide Therapeutic. Proc Natl Acad Sci USA. 2010 Aug 10; 107(32): 14093-8.

International Patent Application PCT/US2011/043465

A stapled BAD peptide protects β cells and restores

β mass in T1D

• DFCI 1126• Type: Stapled peptide• Target: Glucokinase (diabetes)• Investigator: Loren Walensky, MD, PhD & Nika

Danial, PhD• Development stage: POC in in vivo model• Patent status: Methods of Modulating Cellular

Homeostatic Pathways and Cellular Survival (Pending and Granted, e.g., European Patent No. 2152294 and U.S. Patent Application Publication No. 20100273704, from International Patent Application PCT/US2008/062345, claiming priority from May 2, 2007).

• Competitive advantage: Developed a stapled BAD peptide that enhances both the survival and glucose responsiveness of insulin-producing β-cells for type 1 diabetes (T1D); stapled peptide treatment improved engraftment of donor islets into transplanted diabetic mice, increased β-cell viability in islet grafts, restored insulin release, and reversed diabetic symptoms.


Ljubicic S, Polak F, Fu A, Wiwczar J, Szlyk B, Chang Y, Alvarez-Perez JC, Bird GH, Walensky LD, Garcia-OcañaA, Danial NN. Phospho-BAD BH3 mimicry protects β cells and restores functional β cell mass in diabetes. Cell Rep. 2015 Feb 3; 10(4): 497-504.

Reactivating apoptosis in cancer using stapled

peptides

• DFCI 1314

• Type of technology: stapled peptide• Target: BCL-2 family proteins (apoptosis)• Investigator: Loren Walensky, MD, PhD• Development stage: POC in in vivo models• Patent status: Stabilized Alpha Helical Peptides and

Uses Thereof (Pending and Granted, e.g., U.S. Patent Nos. 7,723,469; 8,198,405; 8,796,418; 9,273,099; and 9,464,115, from International Patent Application PCT/US2004/038403, claiming priority from Nov. 5, 2003); Methods and compositions for specific modulation of MCL-1 (Pending and Granted, e.g., U.S. Patent Nos. 9,079,970 and 9,505,816, from International Patent Application PCT/US2009/067363, claiming priority from Dec. 9, 2008).

• Competitive advantage: maintains bioactive structure, resists proteolytic degradation in vivo, increased receptor potency, multimodal target engagement (selective, dual, multiple) – a key advantage over small molecule modulators, gain-of-function and loss-of-function modalities.


Rezaei Araghi et al. Iterative optimization yields Mcl-1 targeting stapled peptides with selective cytotoxicity to Mcl-1-dependent cancer cells. Proc Natl Acad Sci U S A. 2018 Jan 30; 115(5):E886-E895.

Blocking chemotherapy-induced peripheral

neuropathy

• DFCI 1529

• Type of technology: Stapled BH4 peptides• Target: IP3R1 (Ca2+ signaling)• Investigator: Loren Walensky, MD, PhD• Development stage: late lead optimization• Patent status: BH4 Stabilized Peptides and Uses

Thereof (Pending, e.g., U.S. Patent Application Publication No. 20160031959, from International Patent Application PCT/US2014/029318, claiming priority from Mar. 15, 2013).

• Competitive advantage: maintains bioactive structure, resists proteolytic degradation, increased binding potency, unique mechanism for targeted inhibition of pro-apoptotic BAX. Broad applications in blocking unwanted cell death in the context of neurodegeneration, stroke, heart attack, and cancer treatment.

• Key publication:Pease-Raissi SE, Pazyra-Murphy MF, Li Y, Wachter F, Fukuda Y, Fenstermacher SJ, Barclay LA, Bird GH, Walensky LD, Segal RA. Paclitaxel Reduces Axonal Bclwto Initiate IP3R1-Dependent Axon Degeneration. Neuron. 2017 Oct 11; 96(2):373-386.

A covalent stapled peptide selective for BFL-1

• DFCI 2020

• Type: Covalent stapled peptide• Target: Anti-apoptotic BFL-1 protein (apoptosis)• Investigator: Loren Walensky, MD, PhD• Development stage: late lead optimization• Patent status: Inhibition of MCL-1 and/or BFL-1/A1

(Pending and Granted, e.g., U.S. Patent No. 9,926,306, from International Patent Application PCT/US2013/031705, claiming priority from Mar. 20, 2012); Peptides Binding to BFL-1 (Pending from International Patent Application PCT/US2016/049095, claiming priority from Mar. 20, 2012).

• Competitive advantage: selective targeting of anti-apoptotic BFL-1, dual targeting of anti-apoptotic MCL-1 and BFL-1. Versatile targeting spectrum that includes exclusive covalent targeting of BFL-1, or dual targeting of BFL-1 (covalent) and MCL-1 (noncovalent). Strategy broadly applies to therapeutic targets with native cysteines in and around the target binding site.

• Key publication:Huhn AJ, Guerra RM, Harvey EP, Bird GH, Walensky LD. Selective targeting of anti-apoptotic BFL-1 by a covalent stapled peptide inhibitor. Cell Chem Biol. 2016 Sep 22;23(9):1123-34.

Stapled peptide targeting EZH2-EED complex

• DFCI 1681

• Type: Stapled peptide• Target: EED (epigenetics)• Investigator: Loren Walensky, MD, PhD• Development stage: late lead optimization• Patent status: Stabilized EZH2 Peptides (Pending,

e.g., U.S. Patent Application Publication No. 20160068834 from International Patent Application PCT/US2014/025587, claiming priority from Mar. 15, 2013).

• Competitive advantage: Selectively inhibit H3 Lys27 trimethylation by dose-responsively disrupting the EZH2–EED complex and reducing EZH2 protein levels, a mechanism distinct from that reported for small-molecule EZH2 inhibitors targeting the enzyme catalytic domain.


Kim KH, Kim W, Howard TP, Vazquez F, Tsherniak A, Wu JN, Wang W, Haswell JR, Walensky LD, Hahn WC, OrkinSH, Roberts CW. SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2. Nat Med. 2015 Dec; 21(12):1491-6.

Stabilized SOS1 peptide targets mutant and

overexpressed WT KRAS• DFCI 1680

• Type: Stapled peptide• Target: KRAS (cancer)• Investigator: Loren Walensky, MD, PhD• Development stage: late lead optimization• Patent status: Stabilized SOS1 Peptides (Pending,

e.g., U.S. Patent Application Publication No. 20160046671, from International Patent Application PCT/US2014/028436, claiming priority from Mar. 15, 2013).

• Competitive advantage: maintains bioactive structure, resists proteolytic degradation in vivo, increased binding potency, targets broad spectrum of KRAS mutants, including overexpressed wild-type KRAS.


Leshchiner ES, Parkhitko A, Bird GH, Luccarelli J, Bellairs JA, Escudero S, Opoku-Nsiah K, Godes M, Perrimon N, and Walensky LD. Direct inhibition of oncogenic KRAS by hydrocarbon-stapled SOS1 helices. Proc Natl Acad Sci USA. 2013 2015. 112 (6) 1761-1766.

Double-stapled RSV peptide prevents nasopulmonary

infection

• DFCI 1523

• Type: Stapled peptide• Target: RSVF (RSV infection)• Investigator: Loren Walensky, MD, PhD• Development stage: POC in in vivo model• Patent status: Stabilized Antiviral Fusion Helices

(Pending, e.g., U.S. Patent Application Publication No. 20140370042, from International Patent Application PCT/US2012/072315, claiming priority from Dec. 29, 2011); Compositions and Methods for the Treatment of Viral Infections (Pending and Granted, e.g., U.S. Patent No. 9,290,545, from International Patent Application PCT/US2009/000438, claiming priority from Jan. 23, 2008).

• Competitive advantage: Intranasal delivery of a lead double-stapled RSV peptide effectively prevented viral infection of the nares, and a chitosan-based nanoparticle preparation markedly enhanced pulmonary delivery, further preventing spread of nasal RSV infection to the lung; strategy broadly applies to viruses that harness a six helix fusogenic bundle mechanism for host cell infection (RSV, Ebola, MERS, SARS).


Bird et al. Mucosal delivery of a double stapled RSV peptide prevents nasopulmonary infection. J Clin Invest. 2014 May 1; 124(5): 2113-24.

Structured antigen strategy for HIV-1 vaccine

development

• DFCI 1371

• Type: Stapled peptide• Target: HIV-1 (vaccine)• Investigator: Loren Walensky, MD, PhD• Development stage: late lead optimization• Patent status: Structured Viral Peptide Compositions

and Methods of Use (Pending and Granted, e.g., U.S. Patent No. 9,822,165, from International Patent Application PCT/US2010/039223, claiming priority from June 18, 2009).

• Competitive advantage: Developed a series of differentially-stapled structured antigens modeled after the membrane proximal external region of HIV-1 gp41; recapitulates antigenic structures that elicit neutralizing HIV-1 antibodies in long term non-progressor (LTNP) HIV-1 positive patients (4E10, 10E8); structured antigen strategy broadly applies to other vaccine designs.

• Key publication:Bird GH, Irimia A, Ofek G, Kwong PD, Wilson IA, Walensky LD. Stapled HIV-1 peptides recapitulate antigenic structures and engage broadly neutralizing antibodies. Nat Struct Mol Biol. 2014 Dec; 21(12): 1058-67.

Antimicrobial stapled peptides • DFCI 2019, 2168, 2299

• Type: Stapled peptide• Target: Multidrug resistant bacteria• Investigator: Loren Walensky, MD, PhD• Development stage: late lead optimization• Patent status: Stabilized Anti-Microbial Peptides

(Pending, e.g., U.S. Patent Application Publication No. 20170015716, from International Patent Application PCT/US2016/040849, claiming priority from Jul. 2, 2015); Stapled Intracellular-Targeting Antimicrobial Peptides to Treat Infection (Pending, e.g., U.S. Patent Application Publication No. 20170247423, from International Patent Application PCT/US2017/019953, claiming priority from Feb. 29, 2016).

• Competitive advantage: bacterial membrane lytic peptides, structurally-stabilized and protease resistant, selective for bacteria, nontoxic to mammalian membranes, overcome multidrug resistance; bacterial selectivity and proteolytic stability enable internal use; antibacterial stapled peptides in this class overcomes all known bacterial resistance mechanisms, including colistin-resistance.

Thank you! We look forward to learning about your interests!

For inquiries about partnering, collaborating and licensing please contact:Janet Ralbovsky, Ph.D.

Innovation and Licensing LeadBelfer Office for Dana-Farber Innovations

Dana-Farber Cancer [email protected]

June 2018

bio june 2018 - dana–farber cancer institute · patent no. 5937968 and u.s. patent application...

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