Neutral analogs of the heat shock protein 70 (Hsp70) inhibitor, JG-98

Article abstract of DOI:10.1016/j.bmcl.2020.126954

The heat shock protein 70 (Hsp70) family of molecular chaperones are highly expressed in tumors. Inhibitors containing a pyridinium-modified benzothiazole, such as JG-98, bind to a conserved, allosteric site in Hsp70, showing promising anti-proliferative activity in cancer cells. When bound to Hsp70, the charged pyridinium makes favorable contacts; however, this moiety also increases the inhibitor's fluorescence, giving rise to undesirable interference in biochemical and cell-based assays. Here, we explore whether the pyridinium can be replaced with a neutral pyridine. We report that pyridine-modified benzothiazoles, such as compound 17h (JG2-38), have reduced fluorescence, yet retain promising anti-proliferative activity (EC₅₀ values ~0.1 to 0.07 μM) in breast and prostate cancer cell lines. These chemical probes are expected to be useful in exploring the roles of Hsp70s in tumorigenesis and cell survival.

Full text of DOI:10.1016/j.bmcl.2020.126954

Bioorganic&MedicinalChemistryLettersxxx(xxxx)xxxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Neutral analogs of the heat shock protein 70 (Hsp70) inhibitor, JG-98
Hao Shao, Jason E. Gestwicki⁎
Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA
A R T I C L E I N F O
A B S T R A C T
Keywords:
The heat shock protein 70 (Hsp70) family of molecular chaperones are highly expressed in tumors. Inhibitors
containing a pyridinium-modified benzothiazole, such as JG-98, bind to a conserved, allosteric site in Hsp70,
showing promising anti-proliferative activity in cancer cells. When bound to Hsp70, the charged pyridinium
makes favorable contacts; however, this moiety also increases the inhibitor’s fluorescence, giving rise to un-
desirable interference in biochemical and cell-based assays. Here, we explore whether the pyridinium can be
replaced with a neutral pyridine. We report that pyridine-modified benzothiazoles, such as compound 17h (JG2-
38), have reduced fluorescence, yet retain promising anti-proliferative activity (EC50 values ~0.1 to 0.07 µM) in
breast and prostate cancer cell lines. These chemical probes are expected to be useful in exploring the roles of
Hsp70s in tumorigenesis and cell survival.
Allosteric inhibitor
Molecular chaperone
Proteostasis
Prostate cancer
Breast cancer
Chemical probe
Anti-cancer agents
Fluorescence
Members of the Hsp70 family of molecular chaperones, including
heat shock protein 72 (Hsp72, HSPA1A) and heat shock cognate 70
(Hsc70, HSPA8), are over-expressed in many cancers.1–3 In tumor cells,
these Hsp70s are part of a multi-protein complex that is not present in
non-transformed cells,4 and which seems to stabilize onco-proteins and
provide resistance to chemotherapy.1,5,6 Consistent with this role,
knockdown of both Hsp72 and Hsc70 leads to preferential cell death in
cancer cells, but not normal epithelia.7 Interestingly, knockdown of
only one family member (e.g. Hsp72 or Hsc70) is typically not sufficient
to initiate apoptosis, suggesting that pan-inhibitors (hereafter referred
to as “Hsp70 inhibitors”) may hold particular promise. Fortunately,
members of the Hsp70 family are highly conserved, with up to 95%
sequence identity.8,9
trial for solid tumors,24 however, modest efficacy (~5 µM) and meta-
bolic instability limited its further exploration. Subsequent studies re-
vealed that MKT-077 binds a distinct allosteric site in Hsp70,25 which is
highly conserved amongst the family members.26 Binding at this al-
losteric site blocks binding to nucleotide-exchange factors (NEFs), al-
though the pocket does not overlap with the NEF-interaction sur-
face.27,28 Leveraging this structural knowledge, a series of medicinal
chemistry campaigns were designed to improve MKT-077, resulting in
analogs such as JG-98 and JG-231 (Fig. 1), with improved anti-pro-
liferative activity and longer lifetimes in rodents.29–31
While JG-98 and its analogs have been useful chemical probes, these
compounds are fluorescent (λexcitation 470 nm/λemission 560 nm). This
photochemical property likely originates from the conjugated π elec-
tron system that encompasses the rhodacyanine and charged pyr-
idinium. This fluorescence property is not favorable, because it inter-
feres with many assays; for example, these compounds cannot be used
in biochemical assays that utilize fluorescence, such as fluorescence
polarization (FP). Here, we set out to design neutral, non-fluorescent
analogs. Specifically, based on findings with the analog YM-08
(Fig. 1),32 we reasoned that replacing the rhodacyanine and/or the
pyridinium might sufficiently reduce fluorescence and enable use of
these chemical probes in a wider range of applications.
Multiple Hsp70 inhibitors with different mechanisms and binding
sites have been explored. For example, VER-15500810,11 and its ana-
logs12–14 bind to Hsp70’s ATP-binding cleft, while YK5 and its ana-
logs15–17 bind a nearby allosteric site. Despite their different binding
sites, these compounds all seem to limit Hsp70’s function by inter-
rupting its nucleotide cycling. Another strategy is to target the protein-
protein interactions between Hsp70 and the other factors that are
present in cancer-associated, multi-protein complexes. For example, the
dihydropyridine, MAL3-10118,19 and its analogs20–22, disrupt binding of
Hsp70 to J-domain proteins (JDPs).
Towards this goal, we first replaced the central rhodacyanine with
either a benzene (compound 4a-b) or thiazole (compound 8a-b). Based
on structural information obtained with JG-98, the central rhodacya-
nine is relatively solvent exposed, yet it sets the position of the other
ring systems (i.e. the benzothiazole) to optimally interact with two deep
Whadwa and colleagues identified the benzothiazole, MKT-077
(Fig. 1), as another promising inhibitor of Hsp70s. This compound has
anti-proliferative activity in multiple cancer cells, with minimal toxicity
in non-transformed cells.23 MKT-077 progressed to a Phase I clinical
⁎ Corresponding author at: UCSF, 675 Nelson Rising Lane, San Francisco, CA 94158, USA.
E-mail address: jason.gestwicki@ucsf.edu (J.E. Gestwicki).
https://doi.org/10.1016/j.bmcl.2020.126954
Received 6 December 2019; Accepted 1 January 2020
0960-894X/©2020ElsevierLtd.Allrightsreserved.
Pleasecitethisarticleas:HaoShaoandJasonE.Gestwicki,Bioorganic&MedicinalChemistryLetters,
https://doi.org/10.1016/j.bmcl.2020.126954

H. Shao and J.E. Gestwicki
Bioorganic&MedicinalChemistryLettersxxx(xxxx)xxxx
Fig. 1. Previously reported benzothiazole rhodacyanine probes.
Scheme 1. Reagents and conditions: (a) PTSA, H2O, 70 °C, 12 h, 60%; (b) Pd(OAc)2 (10 mol%), ( )BINAP (10 mol%), Cs2CO3 (2 mol), toluene, 25–34%; (c) (i) 4 N
HCl aq., reflux, 24 h, 94%; (ii) 10 eq. MnO2, CHC13, 72%; (d) Cu(II)Br, CHC13 + EtOAc, reflux, 12 h, 78%; (e) Substituted thiourea, EtOH, reflux, 2 h, 52–60%.
pockets.26 Thus, compounds 4a-b and 8a-b were created to understand
whether the rhodacyanine might be replaced without interfering with
these contacts. Briefly, the synthesis of compounds 4a-b started from
cyclization of 2-aminothiophenol and 3-bromobenzaldehyde,33 fol-
lowed by Buchwald-Hartwig amination with anilines (Scheme 1). In
contrast, compounds 8a-b were synthesized by reacting 2-aminothio-
phenol with lactic acid, leading to the alcohol which was then oxidized
to ketone 6 with manganese dioxide. Intermediate 6 was brominated
with copper(II) bromide and then reacted with substituted thiourea to
obtain the final products 8a-b. The purified compounds (> 95% HPLC)
were then tested in anti-proliferative assays using cancer cells from
breast (MCF7) and prostate (22Rv1 and PC3). However, we found that
4a-b and 8a-b tended to have worse activity than JG-98 (Table 1), with
IC50 values between ~ 0.7 and 13 µM. Based on this result, we decided
to retain the rhodacyanine in subsequent analogs and turn our attention
to the pyridinium (see Table 2).
bromide (14) to yield compound 15. Deprotection of 15 with aqueous
ammonium hydroxide yielded 16, which was coupled with anilines to
obtain the final products 17a-o. These products were purified by flash
Table 1
Antiproliferative activities of compounds 4a-b and 8a-b.
Compd
R
MCF-7
22RV1
PC3
IC50/μM
IC50/μM
IC50/μM
JG-98
4a
–
0.71
0.22
–
–
13
0.90
13
2.0
4.8
2.2
5.5
1.3
4b
8a
0.71
7.6
0.20
2.1
6.9
0.15
1.4
0.43
0.74
Specifically, we assembled analogs (compounds 17a-o) in which the
pyridinium was replaced with a neutral pyridine, using a previously
reported route (Scheme 2).26,29 Briefly, substituted anilines 9 were
treated with potassium ethyl xanthate, followed by methylation with
iodomethane under basic conditions. The resulting benzothiazoles 10
were first reacted with methyl p-toluenesulfonate and then coupled
with 3-ethylrhodanine to obtain intermediate 12. Intermediate 12 was
further activated by methyl p-toluenesulfonate, followed by condensa-
tion with 1-((1,3-dioxoisoindolin-2-yl)methyl)-2-methylpyridin-1-ium
0.67
8b
3.6
0.60
3.2
0.28
6.7
0.76
2

H. Shao and J.E. Gestwicki
Bioorganic&MedicinalChemistryLettersxxx(xxxx)xxxx
Table 2
Structure and Activity Relationship of Allosteric Hsp70 inhibitors.
Compd
R1
R2
MCF-7
22RV1
PC3
IC50/μM
IC50/μM
IC50/μM
17a
H
o,m’-Me
o, m’-F
o-Me
o-Cl
1.7
0.05
0.49
0.01
1.8
0.43
0.55
0.20
2.0
0.60
17b
H
1.5
1.1
1.2
0.23
0.11
17c
H
0.99
0.75
0.33
0.40
0.65
0.10
0.42
0.71
0.13
1.3
0.47
0.46
0.30
0.48
0.35
0.15
0.41
0.50
0.19
2.3
1.2
17d
H
0.11
0.06
0.10
0.01
0.01
0.03
0.30
0.01
0.25
0.04
0.15
0.05
0.02
0.08
0.08
0.02
0.78
0.36
0.33
0.50
0.07
0.37
0.76
0.10
2.3
0.07
17e
H
o-F
0.02
0.02
0.10
0.01
0.03
0.01
0.01
17f
4-Me
4-Me
4-Me
4-OCH3
4-OCH3
4-OCH3
5-F
o-Me
o-Cl
17g
17h (JG2-38)
17i
o-F
o-Me
o-Cl
17j
17k
o-F
17l
o-Me
o-Cl
0.35
0.15
0.04
0.02
0.94
0.31
0.31
0.06
0.01
17m
17n
5-F
1.3
0.49
0.15
1.2
0.03
0.07
1.2
5-F
o-F
0.23
1.2
0.26
2.2
17o
5-ethyl
o-F
0.10
chromatography (> 95% HPLC) and characterized by LC-MS/MS and
1H NMR (see Supporting Information).
proliferative activity against the breast (MCF7) and prostate cancer
(22Rv1 and PC3) cell lines. Our previous report shows that ortho- and
meta-modification of the benzene ring in JG-98 can increase potency,29
so we initially tested compounds with dimethyl (17a) or difluoro (17b)
substituents at the o- and m’- positions. Indeed, both had modest ac-
tivity against all three cancer cell lines, with IC50 values in the range of
~1 to 2 µM. Removal of the methyl group at the meta position (17c)
further improved activity, especially against 22Rv1 cells
(IC50 ~ 0.5 µM). Accordingly, we tested ortho-substituted analogs with
either electron withdrawing or donating groups at the ortho-position
A key goal of this synthetic effort was to reduce the compound’s
intrinsic fluorescence. To specifically test this idea, compounds 17a-o
(50 µM) were dissolved in aqueous buffer (100 mM Tris buffer with
10% DMSO, pH 7.4), and the emission spectra of these solutions mea-
sured ((λexcitation 470 nm/λemission 520 to 750 nm). We found that all of
the neutral analogs were significantly less fluorescent than JG-98
(Fig. 2).
With these compounds in-hand, we measured their anti-
Scheme 2. Reagents and conditions: (a) (i)
Potassium ethylxanthate, DMF, 140 °C, 4 h; (ii) MeI,
NEt3, EtOH, 80 °C, 1 h; 40–80%; (b) p-Ts0Me, anisole,
125 °C, 4 h, used directly for next step; (c) 3-Ethyl
rhodanine, Net3, MeCN, 25 °C, 4 h, 30–75%; (d) p-
Ts0Me, DMF, 135 °C, 3 h, 50–85%; (e) Net3, MeCN,
70 °C, 3 h, 70–83%; (f) DCM/MeOH (1:3), aq. NH3,
r.t., l h, 79–87%; (g) anilines, Pd2(dba)3/BINAP/t-
BuONa (0.05:0.15:2), toluene, 100 °C, overnight,
38–55%.
3

H. Shao and J.E. Gestwicki
Bioorganic&MedicinalChemistryLettersxxx(xxxx)xxxx
Fig. 2. Compounds 17a-o are less fluorescent than JG-98. The emission spectrum of compounds 17a-o when excited at 470 nM.
(17c-e), revealing that the o-fluorine compound 17e was the most po-
tent of these analogs, with IC50 values ~0.3 µM.
38) was anchored in a deep pocket formed by residues R72, K71, T13,
F150, P147 and T204. In this orientation, the pyridine ring of 17h
(JG2-38) was largely solvent-exposed, but it positioned the benzyl
group into an adjacent hydrophobic pocket. This binding pose might
explain the preference for only small, ortho-substitutions, because this
group is nestled against Y149 and the β-sheet composed of residues
222–226.
Using these ortho-substituents at the benzene ring, we turned our
attention to modifications of the benzothiazole. In JG-98, small alkyl
and halogen substitutions have been reported to increase activity.26
Similarly, we found that a methyl group at the 4-position (17f-h) re-
sulted in approximately 2-fold improvements. For example, compound
17h (JG2-38) had IC50 values of 0.1 µM against MCF7 cells, 0.15 µM in
22Rv1 cells and 0.07 µM for PC3 cells. These values represent a ~7 to
10-fold improvement on JG-98. Replacement of methyl with methoxy
(17i-k) resulted in similar trends, with the o-fluoro analog 17k again
having the best activity (IC50 values ~ 0.1 to 0.19 µM). In JG-98 ana-
logs, the benzothiazole substitution is tolerated on either the 4- or 5-
position.26 Accordingly, we tested the effects of replacing the 4-
methoxy of 17i-k with 5-fluoro groups (17l-n). However, this mod-
ification generally decreased activity (IC50 values 2.3 to 0.15 µM). Si-
milarly, larger substitutions, such as 5-ethyl (17o), did not improve
activity (IC50 values ~2.1 to 0.18 µM).
Finally, it is known that treatment of cancer cells with Hsp70 in-
hibitors leads to degradation of pro-survival proteins, likely because
chaperone function is needed to maintain their folding. To confirm
whether 17h (JG2-38) might share this activity on Hsp70 biomarkers,
we treated 22Rv1 cells for 24 h and then performed western blots for
oncogenic kinases, Akt1, c-Raf-1 and CDK4, and the translation factor
HuR (Fig. 4). The levels of each protein were reduced by ~50%, con-
sistent with Hsp70 inhibition. Moreover, consistent with previous
findings on other Hsp70 inhibitors,29 we found that treatment with 17h
(JG2-38) did not cause a stress response, as measured by the constant
levels of Hsp72 and Hsp90 (Fig. 4). This result is important because
compensatory stress responses have been hypothesized to reduce sen-
sitivity to chaperone inhibitors.
Based on these results, we selected compound 17h (JG2-38) for
further exploration. First, we studied its possible binding pose, using
molecular docking in Schrodinger, as previously described.29 In these
studies, we used the structure of a truncated form of human Hsc70 (PDB
code 3HSC). In the best-predicted models (Fig. 3), compound 17h (JG2-
In summary, we identified 17h (JG2-38) as a less fluorescent Hsp70
inhibitor, which retains anti-proliferative activity (IC50 ~ 0.1 µM) and
the expected effects on Hsp70 “client” proteins, such as oncogenic
Fig. 3. Compound 17h (JG2-38) binds to an allos-
teric site in the nucleotide binding domain of Hsp70.
Compound 17h (JG2-38) and the residues within 5
angs are shown as stick representation. Carbon atoms
of the protein and 17h (JG2-38) are shown in gray
and orange, respectively. Oxygen, nitrogen and sulfur
are shown in red, blue and yellow, respectively. (For
interpretation of the references to colour in this
figure legend, the reader is referred to the web ver-
sion of this article.)
4

H. Shao and J.E. Gestwicki
Bioorganic&MedicinalChemistryLettersxxx(xxxx)xxxx
Fig. 4. Compound 17h (JG2-38) led to degradation
of oncoproteins without eliciting a heat shock re-
sponse. 22-RV1 cells were treated with 17h (JG2-38)
for 24 h at the indicated concentration, lysed and
western blots performed. Results are representative
of at least two independent experiments.
Quantifications shown are averages of at least two
independent experiments and the error bars re-
present S.E.
kinases. Further work will be needed to optimize the metabolic stability
and solubility of this analog for use in animal models, but its improved
photochemical properties are expected to be beneficial in a range of
applications.
14. Pettinger J, Carter M, Jones K, Cheeseman MD. Kinetic optimization of lysine-tar-
geting covalent inhibitors of HSP72. J Med Chem. 2019.
15. Rodina A, Patel PD, Kang YL, et al. Identification of an allosteric pocket on human
Hsp70 reveals a mode of inhibition of this therapeutically important protein. Chem
Biol. 2013;20:1469–1480.
16. Taldone T, Kang YL, Patel HJ, et al. Heat Shock Protein 70 inhibitors. 2. 2,5'-
Thiodipyrimidines, 5-(phenylthio)pyrimidines, 2-(pyridin-3-ylthio)pyrimidines, and
3-(phenylthio)pyridines as reversible binders to an allosteric site on Heat Shock
Protein 70. J Med Chem. 2014;57:1208–1224.
Declaration of Competing Interest
17. Kang YL, Taldone T, Patel HJ, et al. Heat Shock Protein 70 inhibitors. 1. 2,5'-
Thiodipyrimidine and 5-(phenylthio)pyrimidine acrylamides as irreversible binders
to an allosteric site on Heat Shock Protein 70. J Med Chem. 2014;57:1188–1207.
18. Fewell SW, Smith CM, Lyon MA, et al. Small molecule modulators of endogenous and
co-chaperone-stimulated Hsp70 ATPase activity. J Biol Chem.
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
2004;279:51131–51140.
Acknowledgements
19. Wisen S, Bertelsen EB, Thompson AD, et al. Binding of a small molecule at a protein-
protein interface regulates the chaperone activity of Hsp70-Hsp40. ACS Chem Biol.
2010;5(6):611–622.
This work was generously supported by grants from the NIH
(NS059690) and the U.S. Department of Defense (PC180716).
20. Manos-Turvey A, Al-Ashtal HA, Needham PG, et al. Dihydropyrimidinones and
-thiones with improved activity against human polyomavirus family members. Bioorg
Med Chem Lett. 2016;26:5087–5091.
Appendix A. Supplementary data
21. Chiang AN, Liang M, Dominguez-Meijide A, et al. Synthesis and evaluation of es-
terified Hsp70 agonists in cellular models of protein aggregation and folding. Bioorg
Med Chem. 2019;27:79–91.
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.bmcl.2020.126954.
22. Wright CM, Chovatiya RJ, Jameson NE, et al. Pyrimidinone-peptoid hybrid mole-
cules with distinct effects on molecular chaperone function and cell proliferation.
Bioorg Med Chem. 2008;16:3291–3301.
23. Wadhwa R, Sugihara T, Yoshida A, et al. Selective toxicity of MKT-077 to cancer cells
is mediated by its binding to the hsp70 family protein mot-2 and reactivation of p53
function. Cancer Res. 2000;60:6818–6821.
References
24. Propper DJ, Braybrooke JP, Taylor DJ, et al. Phase I trial of the selective mi-
tochondrial toxin MKT077 in chemo-resistant solid tumours. Ann Oncol.
1999;10:923–927.
1. Evans CG, Chang L, Gestwicki JE. Heat Shock Protein 70 (Hsp70) as an emerging
drug target. J Med Chem. 2010;53:4585–4602.
2. Srinivasan SR, Cesa LC, Li X, et al. Heat Shock Protein 70 (Hsp70) suppresses RIP1-
dependent apoptotic and necroptotic cascades. Mol Cancer Res: MCR. 2018;16:58–68.
3. Joshi S, Wang T, Araujo TLS, Sharma S, Brodsky JL, Chiosis G. Adapting to stress –
chaperome networks in cancer. Nat Rev Cancer. 2018;18:562–575.
4. Wang T, Rodina A, Dunphy MP, et al. Chaperome heterogeneity and its implications
for cancer study and treatment. J Biol Chem. 2019;294:2162–2179.
5. Murphy ME. The HSP70 family and cancer. Carcinogenesis. 2013;34:1181–1188.
6. Sherman MY, Gabai VL. Hsp70 in cancer: back to the future. Oncogene.
2015;34:4153–4161.
25. Rousaki A, Miyata Y, Jinwal UK, Dickey CA, Gestwicki JE, Zuiderweg ER. Allosteric
drugs: the interaction of antitumor compound MKT-077 with human Hsp70 cha-
perones. J Mol Biol. 2011;411:614–632.
26. Li XK, Srinivasan SR, Connarn J, et al. Analogues of the allosteric Heat Shock Protein
70 (Hsp70) inhibitor, MKT-077, as anti-cancer agents. ACS Med Chem Lett.
2013;4:1042–1047.
27. Young ZT, Rauch JN, Assimon VA, et al. Stabilizing the Hsp70-tau complex promotes
turnover in models of tauopathy. Cell Chem Biol. 2016;23:992–1001.
28. Rinaldi S, Assimon VA, Young ZT, et al. A local allosteric network in Heat Shock
Protein 70 (Hsp70) links inhibitor binding to enzyme activity and distal protein-
protein interactions. ACS Chem Biol. 2018;13:3142–3152.
7. Powers MV, Clarke PA, Workman P. Dual targeting of HSC70 and HSP72 inhibits
HSP90 function and induces tumor-specific apoptosis. Cancer Cell. 2008;14:250–262.
8. Hunt C, Morimoto RI. Conserved features of eukaryotic hsp70 genes revealed by
comparison with the nucleotide sequence of human hsp70. Proc Natl Acad Sci USA.
1985;82:6455–6459.
29. Shao H, Li XK, Moses MA, et al. Exploration of benzothiazole rhodacyanines as al-
losteric inhibitors of protein-protein interactions with Heat Shock Protein 70
(Hsp70). J Med Chem. 2018;61:6163–6177.
9. Daugaard M, Rohde M, Jaattela M. The heat shock protein 70 family: highly
homologous proteins with overlapping and distinct functions. FEBS Lett.
2007;581:3702–3710.
30. Moses MA, Kim YS, Rivera-Marquez GM, et al. Targeting the Hsp40/Hsp70 cha-
perone axis as a novel strategy to treat castration-resistant prostate cancer. Cancer
Res. 2018;78:4022–4035.
10. Williamson DS, Borgognoni J, Clay A, et al. Novel adenosine-derived inhibitors of 70
kDa heat shock protein, discovered through structure-based design. J Med Chem.
2009;52:1510–1513.
31. Eftekharzadeh B, Banduseela VC, Chiesa G, et al. Hsp70 and Hsp40 inhibit an inter-
domain interaction necessary for transcriptional activity in the androgen receptor.
Nat Commun. 2019;10:3562.
11. Macias AT, Williamson DS, Allen N, et al. Adenosine-derived inhibitors of 78 kDa
glucose regulated protein (Grp78) ATPase: insights into isoform selectivity. J Med
Chem. 2011;54:4034–4041.
32. Miyata Y, Li X, Lee HF, et al. Synthesis and initial evaluation of YM-08, a blood-brain
barrier permeable derivative of the heat shock protein 70 (Hsp70) inhibitor MKT-
077, which reduces tau levels. ACS Chem Neurosci. 2013;4:930–939.
33. Azizi N, Amiri AK, Baghi R, Bolourtchian M, Hashemi MM. PTSA catalyzed simple
and green synthesis of benzothiazole derivatives in water. Monatshefte für Chemie –
Chem Monthly. 2009;140:1471.
12. Pettinger J, Le Bihan YV, Widya M, van Montfort RLM, Jones K, Cheeseman MD. An
irreversible inhibitor of HSP72 that unexpectedly targets lysine-56. Angew Chem Int
Ed. 2017;56:3536–3540.
13. Moseng MA, Nix JC, Page RC. 2- and N6-functionalized adenosine-5'-diphosphate
analogs for the inhibition of mortalin. FEBS Lett. 2019;593:2030–2039.
5