Discovery and Structure-Based Optimization of Benzimidazole

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Discovery and Structure-Based Optimization of BenzimidazoleDerived Activators of SOS1-Mediated Nucleotide Exchange on RAS Timothy Robert Hodges, Jason R. Abbott, Andrew J. Little, Dhruba Sarkar, James M. Salovich, Jennifer Howes, Denis T. Akan, Jiqing Sai, Allison L. Arnold, Carrie Browning, Michael C. Burns, Tammy Sobolik, Qi Sun, Yugandhar Beesetty, Jesse Coker, Dirk Scharn, Heinz Stadtmueller, Olivia W. Rossanese, Jason Phan, Alex G. Waterson, Darryl B. McConnell, and Stephen W. Fesik J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.8b01108 • Publication Date (Web): 11 Sep 2018 Downloaded from http://pubs.acs.org on September 11, 2018

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Journal of Medicinal Chemistry

Biochemistry

ACS Paragon Plus Environment

Journal of Medicinal Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Discovery and Structure-Based Optimization of Benzimidazole-Derived Activators of SOS1Mediated Nucleotide Exchange on RAS

Timothy R. Hodges,◊,† Jason R. Abbott,◊,† Andrew J. Little,◊,†, ₣ Dhruba Sarkar,◊ James M. Salovich,◊ Jennifer E. Howes,◊ Denis T. Akan,◊ Jiqing Sai,◊ Allison L. Arnold,◊ Carrie Browning,◊ Michael C. Burns,◊,₵ Tammy Sobolik,◊,Ω Qi Sun,◊, Ⱡ Yugandhar Beesetty,◊ Jesse A. Coker,◊, ♯ Dirk Scharn,‡ Heinz Stadtmueller,‡ Olivia W. Rossanese,◊,₽ Jason Phan,◊ Alex G. Waterson,§,¥ Darryl B. McConnell,‡ and Stephen W. Fesik*,◊,§,¥ ◊Department

of Biochemistry, §Department of Pharmacology, Vanderbilt University School of Medicine,

Nashville, Tennessee 37232-0146, USA ¥Department ‡Boehringer

of Chemistry, Vanderbilt University, Nashville, Tennessee 37232-0146, USA

Ingelheim RCV GmbH & Co KG, Doktor-Boehringer-Gasse 5-11, 1120 Vienna, Austria

KEYWORDS: RAS, SOS1, Agonist, Cancer.

ABSTRACT: Son of sevenless homologue 1 (SOS1) is a guanine nucleotide exchange factor that catalyzes the exchange of GDP for GTP on RAS. In its active form, GTP-bound RAS is responsible for numerous critical cellular processes. Aberrant RAS activity is involved in ~30% of all human cancers; hence, SOS1 is an attractive therapeutic target for its role in modulating RAS activation. Here, we describe a new series of benzimidazole-derived SOS1 agonists. Using structure-guided design, we discovered small molecules that increase nucleotide exchange on RAS in vitro at sub-micromolar concentrations, bind to SOS1 with low double digit nanomolar affinity, rapidly enhance cellular RAS-GTP levels, and invoke biphasic signaling changes in phosphorylation of ERK 1/2. These compounds represent the most potent series of SOS1 agonists reported to date.

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■ INTRODUCTION RAS proteins act as molecular switches, cycling between active (GTP-bound) and inactive (GDPbound) states in order to regulate multiple intracellular signaling pathways that control cell proliferation, growth, differentiation, and survival.1,2 Deregulation of these pathways via oncogenic RAS mutations can result in cells displaying many of the hallmarks of cancer and is implicated in the oncogenesis and progression of ~30% of all malignant tumors.3–7 Therefore, therapeutic targeting of oncogenic RAS has been an important and long-standing goal in modern drug discovery. Unfortunately, only limited success has been realized when directly targeting RAS due to the lack of chemically tractable pockets on the protein surface.8–10 The recalcitrant nature of these proteins toward traditional drug discovery strategies has inspired the pursuit of alternative approaches to inhibit RAS signaling.11–19 One strategy is to indirectly target RAS through therapeutic modulation of the regulatory proteins that control its activity. The conversion of RAS-GDP to RAS-GTP is the rate-limiting step in the activation of RAS signaling and is controlled by guanine nucleotide exchange factors (GEFs) such as son of sevenless homologue 1 (SOS1).7,20,21 Due to its importance in RAS signaling, SOS1 has emerged as an attractive therapeutic target for the treatment of RAS-driven cancers.22,23 Our group recently reported two unrelated chemical series that bind to the same hydrophobic pocket on SOS1 as part of a RAS:SOS1:RAS complex.24–26 We have previously shown that these compounds activate nucleotide exchange on RAS, resulting in increased levels of cellular RAS-GTP and, at low concentrations, enhance phosphorylation of extracellular regulared kinase (ERK) 1/2 via the RASMAPK signaling pathway.27 At higher doses of compound, phosphorylated ERK (pERK) phosphorylates SOS1 leading to disruption of the SOS1-GRB2 complex and dissociation of RAS from SOS1, thereby achieving a compound-mediated negative feedback loop that results in reduced ERK phosphorylation. Although seemingly counterintuitive, a growing body of evidence suggest that activation of RAS may be a viable therapeutic strategy.28–30 The “Goldilocks principle” suggests that cells can only tolerate changes in signaling that stay within certain parameters, which do not go either above, or below a certain cellular threshold.31 For example, enhancement of RAS-GTP levels in the cell by ectopic overexpression of mutant RAS can lead to pronounced anti-tumoral responses.32 Furthermore, naturally occurring concomitant expression of mutant RAS with either mutant BRAF or mutant EGFR is very rare, and overexpression of

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RAS is synthetically lethal in the context of an EGFR or BRAF mutation.33–35 Thus, the RAS activation that we observe with SOS1 agonists may represent a promising approach for targeting cells with underlying oncogenic RAS, BRAF, or EGFR mutations. Here, we describe the structure-guided design, synthesis, and structure–activity relationships (SAR) of a new benzimidazole-derived series of SOS1 ligands. These efforts led to the discovery of molecules that robustly activate SOS1-mediated nucleotide exchange in vitro, bind with high affinity to SOS1, rapidly increase cellular RAS-GTP levels, and modulate ERK phosphorylation in cells, resulting in the most potent SOS1 agonists yet reported. ■ RESULTS AND DISCUSSION Discovery of Benzimidazole-Derived SOS1 Compounds. In order to identify compounds that bind to SOS1 and affect SOS1-mediated nucleotide exchange in vitro, we conducted a high throughput screen (HTS) of the Vanderbilt Compound Collection.36 This screen revealed multiple molecules in different chemical series that elicited robust and reproducible SOS1mediated activation of nucleotide exchange on RAS. Similar to our previously reported work,24–26,36 compound efficacy is described by relative percent activation (Act.), which is the rate of nucleotide exchange at the maximum compound dose of 100 µM, relative to the previously reported indole-derived control compound at the same concentration in the same run of the assay.25 The corresponding potency is described as the half maximal effective concentration (EC50) determined from the dose response curve (0– 100 µM of compound) generated from the nucleotide exchange assay. From the HTS hits, several benzimidazole-containing molecules emerged as potentially useful starting points. For example, compounds 1 and 2 were found to activate nucleotide exchange with EC50 values of 63.0 µM and 23.2 µM, respectively (Figure 1A). An early follow-up analog, 3, was synthesized that removed the ring constraints from the 2-position nitrogen atom and introduced a substitution pattern on the benzyl group similar to that of an aniline ring system in a previously reported anilinoquinazoline series.26 These structural modifications afforded a 3-fold improvement in nucleotide exchange activation EC50 when comparing derivative 3 to 2. Furthermore, an X-ray co-crystal structure obtained of 3 bound to the RAS:SOS1:RAS ternary complex confirmed that it binds in the same hydrophobic pocket of the CDC25 domain of SOS1, adjacent to the Switch II region of RAS, that is utilized by previously reported series of SOS1 ligands (Figure 1B).23–26,36 3


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Figure 1. (A) Early hit benzimidazole-derived activators of SOS1-mediated nucleotide exchange. (B) X-ray co-crystal structure of 3 (yellow; PDB ID code 6D5V) bound to SOS1 in the RAS:SOS1:RAS ternary complex. The RAS and SOS1 protein surfaces are colored yellow and grey, respectively. Areas identified for SAR development are highlighted, including: (i) a water-mediated interaction between the 2-amine functionality with Asp887 (blue oval), (ii) occupation of a hydrophobic subpocket beneath Phe890 (red arrows), (iii) occupation of a hydrophobic region along the wall of the CDC25 domain (pink rectangle), (iv) occupation of a hydrophobic subpocket behind Glu902 and adjacent to Phe890 (green circle), and (v) interaction with proximal residues of SOS1 from the 4-position of the benzimidazole scaffold (white arrows).

C-2 Substituent SAR. Analysis of the X-ray co-crystal structure of compound 3 revealed several opportunities to improve binding to SOS1 (Figure 1B).

We initiated our SAR studies by focusing on the 2-position of the

benzimidazole core with the goal of deploying a Lewis base closer to Asp887 in an attempt to establish a direct, rather than water-mediated, interaction (Table 1). Notably, improved potency and efficacy were observed with several 2-amine variants. This was highlighted by 2-piperazino 10, which demonstrated a ~4-fold and ~3-fold improvement in nucleotide exchange EC50 and relative percent activation, respectively. Conversely, negligible nucleotide exchange activation was observed when the Lewis base was removed, as exemplified by 2H-benzimidazole 4. The X-ray co-crystal structure of compound 10 (Figure 2A) revealed that the piperazine moiety occluded the water molecule that facilitated the hydrogen bonding interaction between Asp887 and 3. As a result, the piperazine nitrogen atom of 10 achieved a direct charge–charge interaction with the carboxylate side chain of Asp887. Based on its combination of potent and efficacious

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nucleotide exchange activity and limited number of hydrogen bond donors,37 piperazino-analog 10 was selected as a template for continued structural modification. Table 1. 2-Amino Substituents

Compd

R2

EC50 (µM)

Act. (%)a

3

NH2

8.1 ± 6.83

79 ± 8.0

4

H

--b

--

5

37.1 ± 12.57 129 ± 1.8

6

26.0 ± 0.80 143 ± 18.9

7

8.5 ± 2.06

176 ± 10.1

8

6.6 ± 0.05

114 ± 6.3

9

5.6 ± 0.11

128 ± 0.6

10

2.2 ± 0.52

211 ± 20.5

11

1.9 ± 0.62

114 ± 12.2

Measurements are reported as the mean ± SD of two or more independent experiments, each conducted in duplicate. aActivation

values represent percentage relative to control. 25

b

“--“ denotes an EC50 value of >100 μM, an EC50 value

that was not calculated due to low efficacy, or an activation value that was not determined due to low efficacy.

Benzyl Substituent SAR. With improvements in potency and efficacy achieved via the inclusion of the 2-piperazine moiety, we turned our focus to investigating the chemical space around the benzyl group (Table 2). While orthosubstitutions were generally poorly tolerated (not shown), the contribution of the aromatic halogen atoms in other positions was quite evident, as unsubstituted benzyl analog 12 showed an EC50 that was ~4-fold worse than 10. Interestingly, of the 4’-monosubstituted derivatives, only the 4’-fluoro compound 13 demonstrated improved nucleotide exchange potency relative to 12, and the activity dropped off sharply with larger 4’-moieties. The benefit of meta-substitution also appeared to be limited by size as evidenced 5


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by the drop in potency observed for compounds featuring a 3’-trifluoromethyl (19) or a 3’-cyclopropyl (20) group relative to 10. Together, these data suggested that limited steric bulk at the para- and meta-positions provided improved potency. We noted that compound potency (EC50) was observed to correlate poorly with compound efficacy (Act.). Empirically, it had been previously determined that SOS1 agonists achieving Act. values greater than ~50% elicited more robust increases in cellular RAS–GTP levels.36 Beyond this perceived minimum threshold, the origin and consequences of varying degrees of percent relative activation is not well understood and is currently under further investigation. Table 2. Benzyl Substituents

Compd

R3’

R4’

R5’

EC50 (µM)

Act. (%)a

10

Cl

F

H

2.2 ± 0.52

211 ± 20.5

12

H

H

H

8.6 ± 1.64

122 ± 17.8

13

H

F

H

5.9 ± 4.88

130 ± 28.1

14

H

Cl

H

12.4 ± 2.70

164 ± 15.0

15

H

Me

H

36.6 ± 17.26

93 ± 13.0

16

H

CF3

H

19.6 ± 5.01

148 ± 30.7

17

F

F

H

5.9 ± 1.33

183 ± 25.3

18

Me

F

H

4.1 ± 2.00

190 ± 20.6

19

CF3

F

H

8.1 ± 0.52

263 ± 52.5

F

H

11.7 ± 2.74

151 ± 5.0

F

Me

3.7 ± 0.29

270 ± 73.8

20 21

Me


values represent percentage relative to control.25

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Arene 5,6-Substitution SAR.

Figure 2. (A) X-ray co-crystal structure of 10 (magenta; PDB ID code 6D5M) bound to SOS1 in the RAS:SOS1:RAS ternary complex. The curved blue line highlights the subpocket near His905. The RAS and SOS1 protein surfaces are colored yellow and grey, respectively. (B) 28 (green; PDB ID code 6D5L) overlaid with 10. The green sphere represents space filling of the 6-chlorine atom in 28, whereas the magenta and white spheres represent space filling of the 6methyl group in 10.

Having learned much about the tolerance of substitution around the benzyl group, we transitioned to examining various hydrophobic substitutions at the 5- and 6-positions of the benzimidazole core to optimize the occupancy of the small hydrophobic subpocket near His905 (Figure 2A). For this, the 2piperazino and 3’-chloro-4’-fluoro benzyl moieties were held constant to isolate the effects of the 5- and 6positions of the benzimidazole nucleus (Table 3). Removal of the 5-position substituent had a relatively minor effect on compound potency. Compare, for example, the 5H-6-methyl derivative, 24, and the 5H-6chloro derivative, 28, to their respective 5-methyl analogs 10 and 22. It is interesting to note however, that 5H-substitution resulted in a strong decrease in relative percent activation. The X-ray co-crystal structure of 28 overlaid with that of 10 (Figure 2B) showed that both ligands rest in the hydrophobic subpocket near His905 and effected minimal differences in the positioning of the SOS1 binding pocket residues. This suggested that the differences in observed Act. levels between analogs 10 and 28 are not due to a significant discrepancy in compound binding mode. From these same co-crystal structures, it is apparent that there is little room in the hydrophobic subpocket near His905 for 6-position moieties much larger than a methyl group. This observation is supported by the substantial loss in potency observed for the 6cyclopropyl compound 26. Notably, removal of both 5- and 6-substitution, exemplified by compound 23, 7


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resulted in a ~5-fold reduction in potency relative to 28. These data suggested that an appropriately sized 6-substituent was the primary contributor to potency in this region of the binding pocket.

Table 3. 5,6-Substituents

Compd

R5

R6

EC50 (µM)

Act. (%)a

10

Me

Me

2.2 ± 0.52

211 ± 20.5

22

Me

Cl

3.0 ± 0.56

200 ± 13.3

23

H

H

5.4 ± 1.22

109 ± 4.2

24

H

Me

2.4 ± 0.33

106 ± 13.1

25

H

CF3

4.4 ± 0.54

78 ± 2.2

26

H

24.3 ± 5.33

65 ± 2.2

27

H

Br

1.3 ± 0.3

115 ± 5.4

28

H

Cl

1.0 ± 0.16

109 ± 1.0


values represent percentage relative to control. 25

The SAR developed in Tables 2 and 3 prompted the synthesis of several matched pairs of analogs to investigate the interplay between substituents on the aromatic ring of the benzyl moiety and the substituents at the 5- and 6-positions of the benzimidazole nucleus. From this effort, crossover analog 29— containing the 3’,5’-dimethyl-4’-fluorobenzyl moiety and a 6-position chlorine atom—was found to exhibit an EC50 value below 1 µM in the nucleotide exchange assay (Figure 3A). As compounds continued to improve, we observed a loss of SAR texture for derivatives with EC 50 values in this range. To effectively differentiate more potent compounds, a fluorescence polarization anisotropy (FPA) assay, based on the displacement of a labeled probe from SOS1 (Supplementary Figure S2), was developed to provide a measurement of binding affinity (Κd) to SOS1.38,39 Several earlier compounds were re-evaluated using this FPA assay, showing a general agreement between Κd and nucleotide exchange EC50 for previously 8



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investigated SAR trends (Supplementary Figure S3 and Table S1). This reaffirmed our established SAR and prompted a switch to the FPA assay as the primary tool for evaluating analogs. Moving forward with a new biochemical assay to drive optimization, compound 29 was selected as a template upon which to conduct further work.

Figure 3. (A) Nucleotide exchange and binding affinity data for compound 29. (B) X-ray co-crystal structure of compound 29 (teal; PDB ID code 6D5J) bound to SOS1 in the RAS:SOS1:RAS ternary complex. The red dotted spheres represent molecules of water and the space they occupy. The RAS and SOS1 protein surfaces are colored yellow and grey, respectively.

C-4 Substituent SAR.

The binding mode of compound 29 (Figure 3B) highlighted several opportunities for continued optimization. First, a largely hydrophobic space proximal to the 4-position of the benzimidazole remained unoccupied, as demonstrated by the two molecules of water occupying the back of the binding pocket. Additionally, several residues at the lip of the binding pocket, primarily Glu902, His905, and Tyr884, seemed accessible for interaction. As these regions are largely solvent-exposed, a considerable tolerance for groups that may offer the ability to tune the overall molecular properties was expected. To exploit these opportunities, we explored a wide range of chemical diversity at the 4-position. A selection of these results is shown in Table 4. In an effort to fill the neighboring hydrophobic subpocket, several biaryl derivatives with lipophilic substitutions were synthesized and evaluated by FPA (Table 4). Multiple 4-phenyl analogs demonstrated improved binding affinity relative to the 4H-parent 29. In some instances, ortho-substitution of the 4-phenyl 9


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ring offered further enhancement—best exemplified by the ortho-trifluoromethyl analog 35 and the orthochloro compound 38—relative to the unsubstituted phenyl derivative 30. Increasing the size of the orthoalkyl groups resulted in a decline in binding affinity from 30, suggesting that the nearby pocket has a limited size tolerance. Notably, biaryl analogs, such as 36 and 37, bearing meta- or para-substituents exhibited diminished affinity when compared to their ortho-substituted or unsubstituted comparators. Analysis of the X-ray co-crystal structure of 38 revealed that the aryl group is rotated out of plane from the benzimidazole scaffold (Figure 4A). Further, when the co-crystal structure of 38 was overlaid with that of 29 (Figure 4D), it was evident that 38 leaned over into the SOS1 binding pocket to drive the orthochlorine atom down into the available lipophilic space, thus displacing the previously bound waters from this subpocket. The presence of the hydrophobic aryl group in 38 disrupted the positioning of Glu902, rotating the carboxylic acid side chain upward toward solvent compared to the downward pose observed in the co-crystal structure of 29. The observed gains in binding affinity from the addition of phenyl groups at the 4-position corresponded with an increase in compound lipophilicity as evidenced by a rise in ALogP and correspondingly poor lipophilic ligand efficiency (LipE) 40 when compared with the 4H-compound, 29.

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Table 4. C-4 SAR

Κ d (µM)a

AlogP

LipE

Compd

Κ d (µM)b

AlogP

LipE

Compd

0.46 ± 0.078

5.10

1.23

39

0.30 ± 0.078

7.59

-1.06

30

0.27 ± 0.005

6.62

-0.06

40

0.20 ± 0.003

6.18

31

0.21 ± 0.010

b

7.11

-0.44

41

0.13 ± 0.030

32

0.21 ± 0.029

7.56

-0.88

42

33

0.39 ± 0.093

7.82

-1.41

43

34

0.44 ± 0.139

7.90

-1.54

35

0.15 ± 0.048

7.56

36

0.67 ± 0.007

37

38

4

Compd

R

29

H

Κ d (µM)b

AlogP

LipE

49

0.14 ± 0.009

6.02

0.85

0.51

50

0.24 ± 0.056

5.47

1.16

4.95

1.95

51

0.33 ± 0.027

a

5.47

1.01

0.14 ± 0.013

5.22

1.65

52

0.45 ± 0.104

5.43

0.92

0.25 ± 0.057

a

5.14

1.46

53

0.39 ± 0.064

4.75

1.66

44

0.24 ± 0.083

a

4.41

2.21

54

0.35 ± 0.001

4.84

1.61

-0.74

45

0.31 ± 0.083

5.22

1.30

55

0.11 ± 0.018

5.12

1.82

7.56

-1.39

46

0.38 ± 0.025

5.22

1.20

56

0.10 ± 0.011

6.25

0.74

1.05 ± 0.056

7.56

-1.59

47

0.14 ± 0.009

4.93

1.92

57

0.18 ± 0.081

5.06

1.68

0.12 ± 0.034

7.29

-0.43

48

0.24 ± 0.036

4.93

1.69

58

Discovery and Structure-Based Optimization of Benzimidazole

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