Development of Dual and Selective Degraders of Cyclin-Dependent Kinases 4 and 6

Article abstract of DOI:10.1002/anie.201901336

Cyclin-dependent kinases 4 and 6 (CDK4/6) are key regulators of the cell cycle, and there are FDA-approved CDK4/6 inhibitors for treating patients with metastatic breast cancer. However, due to conservation of their ATP-binding sites, development of selective agents has remained elusive. Here, we report imide-based degrader molecules capable of degrading both CDK4/6, or selectively degrading either CDK4 or CDK6. We were also able to tune the activity of these molecules against Ikaros (IKZF1) and Aiolos (IKZF3), which are well-established targets of imide-based degraders. We found that in mantle cell lymphoma cell lines, combined IKZF1/3 degradation with dual CDK4/6 degradation produced enhanced anti-proliferative effects compared to CDK4/6 inhibition, CDK4/6 degradation, or IKZF1/3 degradation. In summary, we report here the first compounds capable of inducing selective degradation of CDK4 and CDK6 as tools to pharmacologically dissect their distinct biological functions.

Full text of DOI:10.1002/anie.201901336

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Accepted Article
Title: Development of dual and selective degraders of cyclin-dependent
kinases 4 and 6
Authors: Baishan Jiang, Eric S Wang, Katherine A Donovan, Yanke
Liang, Eric S Fischer, Tinghu Zhang, and Nathanael
Schiander Gray
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201901336
Angew. Chem. 10.1002/ange.201901336
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Development of dual and selective degraders of cyclin-dependent
kinases 4 and 6
Baishan Jiang†, Eric S. Wang†, Katherine A. Donovan, Yanke Liang, Eric S. Fischer, Tinghu Zhang*,
Nathanael S. Gray* [a]
Abstract: Cyclin-dependent kinases 4 and 6 (CDK4/6) are key
regulators of the cell cycle, and CDK4/6 inhibitors are FDA-
approved for treating patients with metastatic breast cancer.
However, due to conservation of their ATP-binding sites,
development of selective agents has remained elusive. Here, we
report imide-based degrader molecules capable of degrading
both CDK4/6, or selectively degrading either CDK4 or CDK6.
We were also able to tune the activity of these molecules
against Ikaros (IKZF1) and Aiolos (IKZF3), well-established
targets of imide-based degraders. We found that in mantle cell
lymphoma cell lines, combined IKZF1/3 degradation with dual
CDK4/6 degradation exhibited enhanced anti-proliferative effects
compared to CDK4/6 inhibition, CDK4/6 degradation, or IKZF1/3
degradation. In sum, we report here the first compounds capable
of inducing selective degradation of CDK4 and CDK6 as tools to
pharmacologically dissect their distinct biological functions.
the target of interest, resulting in the target’s polyubiquitination
and subsequent proteasomal degradation[8]. This strategy has
been deployed to achieve selective degradation using non-
selective ligands. For example, selective degradation of CDK9
was achieved by converting the non-selective CDK inhibitor
SNS-032 into a degrader[9]. We also developed a BRD4
degrader that achieves selectivity versus BRD2 and BRD3 by
exploiting structural differences in the bromodomain/E3 ligase
protein-protein interface[10]
.
Cyclin-dependent kinases 4 and 6 (CDK4/6) regulate the
G1-S cell cycle transition by phosphorylating the tumor
suppressor retinoblastoma (Rb), thereby triggering gene
expression programs that promote S phase entry[1]. As such,
CDK4/6 are attractive targets for cancer therapy, and the dual
CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib have
been FDA approved for treating patients with advanced or
metastatic breast cancer, leading to prolonged progression-free-
survival[2]. These agents are also currently under investigation in
subsets of lung cancers, sarcomas, and lymphomas, such as
mantle cell lymphoma (MCL), that exhibits aberrant cell cycle
progression via activation of CDK4/6[3].
Although CDK4 and CDK6 are highly homologous, CDK4-
and CDK6-specific functions have been reported. For example,
in a mouse model of non-small cell lung carcinoma, genetic
ablation of CDK4 but not CDK6 induced senescence in lung
cancer cells expressing mutant K-Ras[4]. On the other hand,
CDK6-specific functions include participating as part of a
transcription complex that regulates expression of p16INK4a
and VEGF-A[5] and acting as a co-factor for NFκB-dependent
gene expression[6]. We also recently demonstrated that CDK6,
but not CDK4, phosphorylates NFAT family transcription factors
to promote T cell activation and enhance the anti-tumor immune
response[7].
As current CDK4/6 inhibitors target their highly conserved
ATP-binding pockets and are approximately equipotent inhibitors
of both proteins, we hypothesized that achieving selectivity
would require exploiting selectivity determinants outside of the
ATP-binding pocket.
One approach is to develop small
molecule degraders, bifunctional molecules that consist of an E3
ubiquitin ligase-binding moiety and a target-binding moiety
connected via an optimizable linker. Successful degradation
requires induced heterodimerization between the E3 ligase and
[a]
Dr. B. Jiang, Dr. E. S. Wang, Dr. K. A. Donovan, Dr. Y. Liang,
Dr. E. S. Fischer, Dr. T. Zhang, Dr. N. S. Gray
Department of Cancer Biology
Dana-Farber Cancer Institute
Boston, MA (USA)
E-mail: nathanael_gray@dfci.harvard.edu
Dr. B. Jiang and Dr. E. S. Wang contributed equally
Co-corresponding authors
[†]
[*]
Figure 1. Chemical structures of CDK4/6 degraders derived
from palbociclib (A), ribociclib (B), or abemaciclib.
Supporting information for this article is given via a link at the
end of the document.
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compromising affinity to CDK4/6, so we designed palbociclib-,
ribociclib-, and abemaciclib-based degraders using thalidomide
as the CRBN-recruiting moiety (Figure 1). Compounds were
alkylated from the 4-nitrogen of the piperazine, extended with
either a polyethylene glycol (PEG) or an alkyl linker, and
terminated at either the 4-position of thalidomide.
We first assessed the CDK4/6 kinase inhibition activity of
these degraders using enzymatic assays. Most compounds
maintained a biochemical IC50 ranging from 1 – 50 nM (Table
S1), validating our choice of linker attachment site. Next, we
evaluated whether biochemically-active compounds could
degrade CDK4 or CDK6 in Jurkat cells, which express both
proteins, and treated Jurkat cells for 4h with 1 µM of degraders
derived from each CDK4/6 inhibitor: BSJ-02-162 (palbociclib),
Figure 2. Palbociclib-,
ribociclib-, and
abemaciclib-based
degraders induce
CDK4/6 degradation.
Immunoblots from
Jurkat cells treated
with 1 µM oft he
indicated compound
for 4h.
BSJ-01-152
(ribociclib),
or
BSJ-01-184
(abemaciclib).
Immunoblotting for CDK4/6 revealed that each inhibitor could be
successfully converted into active CDK4/6 degraders (Figure 2).
Interestingly, abemaciclib-based degraders also induced
The small molecule thalidomide, which binds to the
ubiquitously expressed E3 ligase substrate adapter Cereblon
(CRBN), has often been used as the E3 ligase-binding moiety in
degraders[11]. Here, we generated CRBN-recruiting degraders
and identified molecules capable of inducing both dual CDK4/6
and selective CDK4 or CDK6 degradation.
High-resolution crystal structures of palbociclib [PDB ID:
5L2I], ribociclib [PDB ID: 5L2T], and abemaciclib [PDB ID: 5L2S]
with CDK6 revealed similar binding modes where the
aminopyrimidine moiety forms three hydrogen bonds with the
backbones of Val101 and Asp163, and the piperazine ring is
stabilized via direct interactions with a solvent-exposed ridge
consisting of Asp104 and Thr107. We hypothesized that we
could attach linkers at the piperazine moiety without
degradation of CDK9, a known off-target[12]
.
Subsequently, we found that acute exposure to some
degraders differentially affected the abundance of CDK4 and
CDK6, as a function of inhibitor, linker length, and linker
composition. For example, BSJ-02-162, which consists of an
alkyl linker conjugated to palbociclib, degraded both CDK4 and
CDK6 (Figure 3A). In contrast, BSJ-01-187, a ribociclib-based
degrader with a 4-carbon alkyl linker, selectively degraded
CDK4 (Figure 3C), while the extended PEG-3 linker of the
palbociclib-derived compound YKL-06-102 induced selective
degradation of CDK6 (Figure 3E).
Figure 3. Variations of linker length and composition result in differing selectivity for CDK4/6 and IKZF1/3 degradation. Immunoblots
from WT or Crbn-/- Jurkat cells treated for 4h with (A) BSJ-02-162; (B) BSJ-03-204; (C) BSJ-01-187; (D) BSJ-04-132; (E) YKL-06-
102; and (F) BSJ-03-123.
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Figure 4. CDK4/6 degrader-induced cell cycle arrest is dependent on CRBN. Representative fluorescence histograms (A) and
quantitation (B) of wildtype or Crbn-/- Jurkat cells treated with 100 nM of indicated compound for 24h and stained with PI.
We also evaluated compound-induced degradation of
IKZF1 and IKZF3, known targets of imides and some imide-
assessed the analogs BSJ-03-204 (Figure 3B; palbociclib-based
dual CDK4/6 degrader), BSJ-04-132 (Figure 3D; ribociclib-based
selective CDK4 degrader), and BSJ-03-123[14] (Figure 3F;
palbociclib-based selective CDK6 degrader), none of which
induced IKZF1/3 degradation. Finally, we found that treatment of
isogenic Jurkat cells in which CRBN was deleted by
CRISPR/Cas9 had no effect on the abundance of CDK4/6
and/or IKZF1/3 protein, demonstrating that that degradation was
dependent on CRBN (Figure 3).
based degraders[13]
, and found that the palbociclib-based
degraders BSJ-02-162 and YKL-06-102 or the ribociclib-based
degrader BSJ-01-187 all induced degradation of IKZF1/3 (Figure
3). As previous studies indicated that varying the thalidomide
aryl amine nitrogen to an oxylamide could prevent recruitment of
IKZF1/3 to CRBN[10, 13c], we investigated whether the equivalent
modification would have the same effect here. Thus, we
Figure 5. Proteome-wide
selectivity of CDK4/6
degrader molecules.
Quantitative proteomics
showing relative abundance
of proteins in Molt4 cells
treated for 5h with 250 nM
of (A) BSJ-02-162; (B) BSJ-
03-204; (C) BSJ-04-132;
and (D) BSJ-03-123.
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Figure 6. Combined CDK4/6 and IKZF1/3 degradation has potent anti-proliferative effects on MCL cell lines. (A) Immunoblots
from Granta-519 cells treated with 1 µM of indicated compounds for 1d. (B) Cell cycle analysis of Granta-519 cells by quantitation of
DNA content after treatment with 1 µM of indicated compounds for 1d. (C) MCL cells were treated with the indicated compounds and
concentrations for 3d (4d for Granta-519). Anti-proliferative effects of compounds were assessed using the CellTiter-Glo assay
(Promega), and ED50s were determined using Graphpad Prism nonlinear regression curve fit.
As CDK4/6 inhibition induces cell cycle arrest, we
compared the effects of the palbociclib-based CDK4/6 and
IKZF1/3 degrader BSJ-02-162 to those of palbociclib or
lenalidomide on the cell cycle profile of wildtype and Crbn-/-
Jurkat cells by quantifying DNA content via propidium iodide
staining (Figure 4). As expected, treatment of wildtype or Crbn-/-
Jurkat cells with 100 nM palbociclib for 24h induced profound G1
arrest in both cell lines, while treatment with 100 nM
lenalidomide for 24h had no effect. In contrast, treatment with
100 nM of BSJ-02-162 for 24h induced G1 arrest in wildtype but
not Crbn-/- Jurkat cells, indicating that the cytostatic effect of
CDK4/6 degraders required CRBN-dependent degradation of
CDK4/6 (Figure 4).
To more broadly assess degrader selectivity, we
performed multiplexed mass spectrometry (MS)-based
proteomic analysis[15] in Molt4 cells treated with 250 nM of BSJ-
02-162, BSJ-03-204, BSJ-04-132 or BSJ-03-123 for 5h. As
expected, BSJ-02-162 induced loss of CDK4/6, IKZF1/3, and
other zinc finger proteins known to be recruited to CRBN by
imides (Figure 5A)[16]. In contrast, its non-IKZF1/3-recruiting
analog BSJ-03-204 was verified to be selective for CDK4/6
degradation (Figure 5B). In cells treated with BSJ-04-132, CDK4
(~1.9-fold change) did not meet our minimum 2-fold change
threshold to be depicted on the scatterplot (Figure 5C), but its
level was reduced to a greater extent than those of CDK6,
IKZF1 and IKZF3 (Table S2). Finally, treatment of Molt4 cells
with BSJ-03-123 resulted in loss of CDK6, but not CDK4 or
IKZF1/3 (Figure 5D). Thus, profiling confirmed that we could
achieve both dual and selective degradation of CDK4/6 across
the proteome after acute compound treatment, and that we
could tune degradation of IKZF1/3.
CDK4/6 inhibitors are currently being evaluated for MCL,
an incurable B cell non-Hodgkin lymphoma whose molecular
hallmark is the t(11;14)(q13;q32) chromosomal translocation that
juxtaposes CCND1 (encoding cyclin D1) with the Ig heavy chain
gene locus, resulting in aberrant cell cycle progression via
activation of CDK4/6[17]
. As such, we examined the effects of
CDK4/6 degraders in several MCL cell lines.
We first tested our CDK4/6 degraders in Granta-519 cells,
a MCL cell line that exhibits the characteristic overexpression of
cyclin D1. Treatment of Granta-519 cells with 1 µM BSJ-02-162
(palbociclib-based) for 1d resulted in pronounced loss of CDK4/6
and IKZF1/3 protein, while treatment with its analog BSJ-03-204
only resulted in degradation of CDK4/6 (Figure 6A). Similar to
palbociclib, these dual CDK4/6 degraders also reduced levels of
phosphorylated Rb (Figure 6A). Finally, treatment of Granta-519
cells with these degraders also potently induced a G1 arrest
(Figure 6B).
Next, we profiled the anti-proliferative activities of BSJ-02-
162 and BSJ-03-204 in comparison with their parent inhibitor
palbociclib and lenalidomide, which itself is FDA-approved for
the treatment of patients with relapsed MCL, in a panel of MCL
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[6] K. Handschick, K. Beuerlein, L. Jurida, M. Bartkuhn, H. Muller,
J. Soelch, A. Weber, O. Dittrich-Breiholz, H. Schneider, M.
Scharfe, M. Jarek, J. Stellzig, M. L. Schmitz, M. Kracht,
Molecular cell 2014, 53, 193-208.
cell lines that exhibit a range of sensitivity to CDK4/6 inhibition.
Interestingly, BSJ-02-162, which degrades CDK4/6 and IKZF1/3,
had increased anti-proliferative effects in many MCL cell lines in
comparison to BSJ-03-204, which only degrades CDK4/6
(Figure 6C), suggesting that co-targeting these two distinct
pathways may be a promising strategy for the treatment of MCL.
In sum, we developed a series of CDK4/6 degraders that
largely recapitulated the cellular effects of CDK4/6 inhibition,
including reduction in pRB levels, G1 arrest, and anti-
proliferative activity. As these effects required the presence of
CRBN, they were dependent on target degradation rather than
inhibition. Similarly, Zhao and Burgess recently reported that
conjugation of pomalidomide to either palbociclib or ribociclib
resulted in degraders that could induce dual degradation of
[7] J. Deng, E. S. Wang, R. W. Jenkins, S. Li, R. Dries, K. Yates, S.
Chhabra, W. Huang, H. Liu, A. R. Aref, E. Ivanova, C. P.
Paweletz, M. Bowden, C. W. Zhou, G. S. Herter-Sprie, J. A.
Sorrentino, J. E. Bisi, P. H. Lizotte, A. A. Merlino, M. M. Quinn,
L. E. Bufe, A. Yang, Y. Zhang, H. Zhang, P. Gao, T. Chen, M. E.
Cavanaugh, A. J. Rode, E. Haines, P. J. Roberts, J. C. Strum,
W. G. Richards, J. H. Lorch, S. Parangi, V. Gunda, G. M.
Boland, R. Bueno, S. Palakurthi, G. J. Freeman, J. Ritz, W. N.
Haining, N. E. Sharpless, H. Arthanari, G. I. Shapiro, D. A.
Barbie, N. S. Gray, K. K. Wong, Cancer Discov 2018, 8, 216-
233.
CDK4/6 and reduce levels of phosphorylated Rb[18]
.
[8] M. Toure, C. M. Crews, Angew Chem Int Ed Engl 2016, 55,
We also discovered that simultaneously degrading CDK4/6
and IKZF1/3 demonstrated enhanced anti-proliferation effect in
MCL cell lines in comparison to palbociclib, lenalidomide, or a
selective CDK4/6 degrader, similar to what was observed with a
1966-1973.
[9] C. M. Olson, B. Jiang, M. A. Erb, Y. Liang, Z. M. Doctor, Z.
Zhang, T. Zhang, N. Kwiatkowski, M. Boukhali, J. L. Green, W.
Haas, T. Nomanbhoy, E. S. Fischer, R. A. Young, J. E. Bradner,
G. E. Winter, N. S. Gray, Nat Chem Biol 2018, 14, 163-170.
[10] R. P. Nowak, S. L. DeAngelo, D. Buckley, Z. He, K. A. Donovan,
J. An, N. Safaee, M. P. Jedrychowski, C. M. Ponthier, M.
Ishoey, T. Zhang, J. D. Mancias, N. S. Gray, J. E. Bradner, E. S.
Fischer, Nat Chem Biol 2018, 14, 706-714.
previously reported BTK degrader that also targeted IKZF1/3[13c]
.
Thus, compounds that target multiple vulnerabilities may be a
promising therapeutic strategy, particularly for B-cell
malignancies that are sensitive to IKZF1/3 degradation.
The highly homologous ATP-binding pockets of CDK4 and
CDK6 has hindered the development of selective CDK4 or
CDK6 probes. Here, by varying the linkers for CDK4/6-targeted
degraders, we identified molecules capable of acutely and
selectively degrading either CDK4 or CDK6. Structural analysis
of kinase-degrader-CRBN ternary complexes will be required to
reveal the basis for the observed selectivity. These compounds
may serve as selective probes for pharmacological dissection of
the distinct CDK4 or CDK6 biological functions and as starting
points for the development of therapeutic degrader molecules.
[11] aS. An, L. Fu, EBioMedicine 2018, 36, 553-562; bP. M. Cromm,
C. M. Crews, Cell Chem Biol 2017, 24, 1181-1190.
[12] L. M. Gelbert, S. Cai, X. Lin, C. Sanchez-Martinez, M. Del
Prado, M. J. Lallena, R. Torres, R. T. Ajamie, G. N. Wishart, R.
S. Flack, B. L. Neubauer, J. Young, E. M. Chan, P. Iversen, D.
Cronier, E. Kreklau, A. de Dios, Invest New Drugs 2014, 32,
825-837.
[13] aG. Lu, R. E. Middleton, H. Sun, M. Naniong, C. J. Ott, C. S.
Mitsiades, K. K. Wong, J. E. Bradner, W. G. Kaelin, Jr., Science
2014, 343, 305-309; bJ. Kronke, N. D. Udeshi, A. Narla, P.
Grauman, S. N. Hurst, M. McConkey, T. Svinkina, D. Heckl, E.
Comer, X. Li, C. Ciarlo, E. Hartman, N. Munshi, M. Schenone,
S. L. Schreiber, S. A. Carr, B. L. Ebert, Science 2014, 343,
301-305; cD. Dobrovolsky, E. S. Wang, S. Morrow, C. Leahy, T.
Faust, R. P. Nowak, K. A. Donovan, G. Yang, Z. Li, E. S.
Fischer, S. P. Treon, D. M. Weinstock, N. S. Gray, Blood 2018;
dH. T. Huang, D. Dobrovolsky, J. Paulk, G. Yang, E. L.
Weisberg, Z. M. Doctor, D. L. Buckley, J. H. Cho, E. Ko, J.
Jang, K. Shi, H. G. Choi, J. D. Griffin, Y. Li, S. P. Treon, E. S.
Fischer, J. E. Bradner, L. Tan, N. S. Gray, Cell Chem Biol 2018,
25, 88-99 e86.
Acknowledgements
The authors gratefully acknowledge the generous financial
support of the following sources: Damon Runyon Cancer
Research Fellowship DRG-2270-16 (E.S.W.). This work was
funded by NIH grant R01CA218278 (E.S.F). Eric S. Fischer is a
Damon Runyon-Rachleff Innovator supported in part by the
Damon Runyon Cancer Research Foundation (DRR-50-18).
Conflicts of Interest
N.S.G. is a founder, science advisory board member (SAB) and
equity holder in Gatekeeper, Syros, Petra, C4, B2S and Soltego.
The Gray lab receives or has received research funding from
Novartis, Takeda, Astellas, Taiho, Janssen, Kinogen, Voronoi,
Her2llc, Deerfield and Sanofi. E.S.F is a founder and/or member
of the scientific advisory board, and equity holder of C4
Therapeutics and Civetta Therapeutics and is a consultant to
Novartis, AbbVie and Deerfield. The Fischer lab receives or has
received research funding from Novartis, Deerfield and Astellas.
B.J., E.S.W., Y.L., T.H.Z., and N.S.G are inventors on patents
covering CDK4/6 degraders owned by Dana-Farber.
[14] M. Brand, B. Jiang, S. Bauer, K. A. Donovan, Y. Liang, E. S.
Wang, R. P. Nowak, J. C. Yuan, T. Zhang, N. Kwiatkowski, A.
C. Muller, E. S. Fischer, N. S. Gray, G. E. Winter, Cell Chem
Biol 2018.
[15] K. A. Donovan, J. An, R. P. Nowak, J. C. Yuan, E. C. Fink, B. C.
Berry, B. L. Ebert, E. S. Fischer, Elife 2018, 7.
[16] aJ. An, C. M. Ponthier, R. Sack, J. Seebacher, M. B. Stadler, K.
A. Donovan, E. S. Fischer, Nat Commun 2017, 8, 15398; bQ. L.
Sievers, G. Petzold, R. D. Bunker, A. Renneville, M. Slabicki, B.
J. Liddicoat, W. Abdulrahman, T. Mikkelsen, B. L. Ebert, N. H.
Thoma, Science 2018, 362.
[17] P. Jares, D. Colomer, E. Campo, Nat Rev Cancer 2007, 7, 750-
762.
Keywords: drug design • cancer • cell cycle • CDK4/6 • protein
degradation
[18] B. Zhao, K. Burgess, Chem Commun (Camb) 2019.
[1] B. O'Leary, R. S. Finn, N. C. Turner, Nat Rev Clin Oncol 2016,
13, 417-430.
[2] B. Laderian, T. Fojo, Semin Oncol 2017, 44, 395-403.
[3] C. J. Sherr, D. Beach, G. I. Shapiro, Cancer Discov 2016, 6,
353-367.
[4] M. Puyol, A. Martin, P. Dubus, F. Mulero, P. Pizcueta, G. Khan,
C. Guerra, D. Santamaria, M. Barbacid, Cancer Cell 2010, 18,
63-73.
[5] K. Kollmann, G. Heller, C. Schneckenleithner, W. Warsch, R.
Scheicher, R. G. Ott, M. Schafer, S. Fajmann, M. Schlederer, A.
I. Schiefer, U. Reichart, M. Mayerhofer, C. Hoeller, S.
Zochbauer-Muller, D. Kerjaschki, C. Bock, L. Kenner, G.
Hoefler, M. Freissmuth, A. R. Green, R. Moriggl, M. Busslinger,
M. Malumbres, V. Sexl, Cancer Cell 2013, 24, 167-181.
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